Compounds that are ERK inhibitors

ABSTRACT

Disclosed are the ERK inhibitors of formula (1): 
                         
and the pharmaceutically acceptable salts thereof. Also disclosed are methods of treating cancer using the compounds of formula (I).

This application is a divisional application based on U.S. patentapplication Ser. No. 15/656,176, and which is a divisional applicationbased on U.S. patent application Ser. No. 14/787,280, now U.S. Pat. No.9,745,307, which is a U.S. national phase under 35 U.S.C. § 371 ofInternational Application No. PCT/US14/035384, filed Apr. 25, 2014,which claims the benefit under 35 U.S.C. § 119(e) to U.S. ProvisionalApplication No. 61/817,571 filed Apr. 30, 2013. The contents of each ofthese applications are incorporated herein by reference in theirentireties.

BACKGROUND OF THE INVENTION

The processes involved in tumor growth, progression, and metastasis aremediated by signaling pathways that are activated in cancer cells. TheERK pathway plays a central role in regulating mammalian cell growth byrelaying extracellular signals from ligand-bound cell surface tyrosinekinase receptors such as erbB family, PDGF, FGF, and VEGF receptortyrosine kinase. Activation of the ERK pathway is via a cascade ofphosphorylation events that begins with activation of Ras. Activation ofRas leads to the recruitment and activation of Raf, a serine-threoninekinase. Activated Raf then phosphorylates and activates MEK1/2, whichthen phosphorylates and activates ERK1/2. When activated, ERK1/2phosphorylates several downstream targets involved in a multitude ofcellular events including cytoskeletal changes and transcriptionalactivation. The ERK/MAPK pathway is one of the most important for cellproliferation, and it is believed that the ERK/MAPK pathway isfrequently activated in many tumors. Ras genes, which are upstream ofERK1/2, are mutated in several cancers including colorectal, melanoma,breast and pancreatic tumors. The high Ras activity is accompanied byelevated ERK activity in many human tumors. In addition, mutations ofBRAF, a serine-threonine kinase of the Raf family, are associated withincreased kinase activity. Mutations in BRAF have been identified inmelanomas (60%), thyroid cancers (greater than 40%) and colorectalcancers. These observations indicate that the ERK1/2 signalling pathwayis an attractive pathway for anticancer therapies in a broad spectrum ofhuman tumours.

Therefore, a welcome contribution to the art would be small-molecules(i.e., compounds) that inhibit ERK activity (ERK2 activity), whichsmall-molecules would be useful for treating a broad spectrum ofcancers, such as, for example, melanoma, pancreatic cancer, thryroidcancer, colorectal cancer, lung cancer, breast cancer, and ovariancancer. Such a contribution is provided by this invention.

SUMMARY OF THE INVENTION

This invention provides compounds that inhibit the activity of ERK2.

Thus, this invention provides compounds that are ERK inhibitors (i.e.,ERK2 inhibitors), said compounds being of the formula (I):

or a pharmaceutically acceptable salt, ester, solvate or prodrugthereof, wherein: Ring B is a 6 or 7 membered ring fused to Ring A(i.e., Ring A and Ring B have two atoms in common), and Q, R¹, R², R³,X, Y and Z are defined below.

This invention provides: (1) compounds of formula (I); (2) compounds offormula (I) in pure or isolated form; (3) pharmaceutically acceptablesalts of the compounds of formula (I); (4) solvates of the compounds offormula (I); (5) compounds of formula (I) wherein from one to all of thehydrogens are deuterium; (6) compounds of formula (I) wherein at leastone H is deuterium; (7) compounds of formula (I) wherein 1 to 5H aredeuterium; (8) compounds of formula (I) wherein 1 to 2H are deuterium;and (9) compounds of formula (I) wherein one H is deuterium.

This invention provides compounds of formula (I) in the free base form.

This invention provides compounds of formula (I) in a pharmaceuticallyacceptable salt form.

This invention also provides compounds (1) to (47).

This invention also provides a pharmaceutical composition comprising aneffective amount of at least one (e.g., 1) compound of formula (I) and apharmaceutically acceptable carrier. This invention also provides apharmaceutical composition comprising an effective amount of at leastone (e.g., 1) pharmaceutically acceptable salt of a compound of formula(I) and a pharmaceutically acceptable carrier. This invention alsoprovides a pharmaceutical composition comprising an effective amount ofat least one (e.g., 1) compound of formula (I) and an effective amountof at least one (e.g., 1) other pharmaceutically active ingredient (suchas, for example, a chemotherapeutic agent), and a pharmaceuticallyacceptable carrier.

This invention also provides a method of inhibiting ERK (i.e.,inhibiting the activity of ERK2) in a patient in need of such treatmentcomprising administering to said patient an effective amount of at leastone (e.g., 1) compound of formula (I). This invention also provides amethod of inhibiting ERK (i.e., inhibiting the activity of ERK2) in apatient in need of such treatment comprising administering to saidpatient an effective amount of at least one (e.g., 1) pharmaceuticallyacceptable salt of a compound of formula (I).

This invention also provides a method for treating cancer in a patientin need of such treatment, said method comprising administering to saidpatient an effective amount of at least one (e.g., 1) compound offormula (I). This invention also provides a method for treating cancerin a patient in need of such treatment, said method comprisingadministering to said patient an effective amount of at least one(e.g., 1) pharmaceutically acceptable salt of a compound of formula (I).This invention also provides a method for treating cancer in a patientin need of such treatment, said method comprising administering to saidpatient an effective amount of at least one (e.g., 1) compound offormula (1), in combination with an effective amount of at least onechemotherapeutic agent. This invention also provides a method fortreating cancer in a patient in need of such treatment, said methodcomprising administering to said patient an effective amount of at leastone (e.g., 1) pharmaceutically acceptable salt of a compound of formula(1), in combination with an effective amount of at least onechemotherapeutic agent. The methods of this invention include theadministration of a pharmaceutical composition comprising at least one(e.g., 1) compound, or pharmaceutically acceptable salt thereof, of thisinvention and a pharmaceutically acceptable carrier. This invention alsoprovides any of the above methods of treating cancer wherein the canceris colorectal. This invention also provides any of the above methods oftreating cancer wherein the cancer is melanoma.

The methods of treating cancers described herein can optionally includethe administration of an effective amount of radiation (i.e., themethods of treating cancers described herein optionally include theadministration of radiation therapy).

DETAILED DESCRIPTION OF THE INVENTION

All patents, publications and pending patent applications identifiedherein are hereby incorporated by reference.

As described herein, unless otherwise indicated, the use of a drug orcompound in a specified period is per treatment cycle. For example, oncea day means once per day of each day of the treatment cycle, and once aweek means one time per week during the treatment cycle.

The following abbreviations have the following meanings unless definedotherwise: Ac is acetyl; ACN is acetonitrile; AcOEt is ethyl acetate;AcOH (or HOAc) is acetic acid; aq is aqueous; atm is atmosphere; Bn (orBN) is benzyl; Boc (or BOC) is tert-butoxycarbonyl; Brettphos is2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl;Brettphos palladacycle is(chloro[2-(dicyclohexylphophino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II);Bu is butyl; Bz is benzoyl; DCE is 1,2-dichloroethane; DCM isdichloromethane; DIPEA (or DIEA or Hunig's Base) isN,N,-diisopropylethylamine; DMF is N,N-dimethylformamide; DMSO isdimethylsulfoxide; Dppf is 1,1′-bis(diphenyl-phosphino)ferrocene; Et isethyl; EtOAc is ethyl acetate; g is grams; h is hour; HPLC is highpressure liquid chromatography; LCMS is liquid chromatography massspectrometry; LG is leaving group; LHMDS or LiHMDS is lithiumhexamethyldisilazide; Me is methyl; MeOH is methanol; mg is milligrams;min is minute; mL is milliliters; mmole is millimoles; MS is massspectrometry; NBS is N-bromosuccinimide; NMR is nuclear magneticresonance spectroscopy; PG is protecting group; Ph (or PH) is phenyl;Pd₂(dba)₃ is tris(dibenzylideneacetone)dipalladium (0); prep meanspreparative; PTLC is preparative thin layer chromatography; Pr ispropyl; RP is reverse-phase; RT (or rt) is room temperature; sat issaturated; SM is starting material; t-butyl is tert-butyl; TEA istriethylamine (Et₃N); TFA is trifluoroacetic acid; THF istetrahydrofuran; TLC is thin layer chromatography; Trt or trityl istriphenyl methane; Xantphos is4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; and μl is microliters.

As used herein, unless otherwise specified, the terms below have themeaning indicated.

Unless otherwise specified, the bond from a fused ring moiety to therest of the molecule can be from any ring of the fused ring moiety.

The term “composition” is intended to encompass a product comprising thespecified ingredients in the specified amounts, as well as any productwhich results, directly or indirectly, from combination of the specifiedingredients in the specified amounts.

The term “anti-cancer agent” means a drug (medicament orpharmaceutically active ingredient) for treating cancer.

The term “antineoplastic agent” means a drug (medicament orpharmaceutically active ingredient) for treating cancer (e.g., achemotherapeutic agent).

The term “at least one” means one or more than one. In one example “atleast one” means 1-4, and in another example 1-3, and in another example1-2, and in another example 1. The meaning of “at least one” withreference to the number of compounds of this invention is independent ofthe meaning with reference to the number of chemotherapeutic agents.

The term “chemotherapeutic agent” means a drug (medicament orpharmaceutically active ingredient) for treating cancer (e.g., anantineoplastic agent).

The term “compound” with reference to the antineoplastic agents,includes the agents that are antibodies.

The term “consecutively” means one following the other.

The term “effective amount” means a “therapeutically effective amount”.The term “therapeutically effective amount” means that amount of activecompound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal or human that is beingsought by a researcher, veterinarian, medical doctor or other clinician.Thus, for example, in the methods of treating cancer described herein“effective amount” (or “therapeutically effective amount”) means, theamount of the compound (or drug), or radiation, that results in: (a) thereduction, alleviation or disappearance of one or more symptoms causedby the cancer, (b) the reduction of tumor size, (c) the elimination ofthe tumor, and/or (d) long-term disease stabilization (growth arrest) ofthe tumor. Also, for example, an effective amount, or a therapeuticallyeffective amount of the ERK inhibitor (i.e., a compound of thisinvention) is that amount which results in the reduction in ERK (ERK2)activity and phosphorylation. The reduction in ERK activity may bedetermined by the analysis of pharmacodynamic markers such asphosphorylated RSK1,2 using techniques well known in the art.

The term “treating cancer” or “treatment of cancer” refers toadministration to a mammal afflicted with a cancerous condition andrefers to an effect that alleviates the cancerous condition by killingthe cancerous cells, and also refers to an effect that results in theinhibition of growth and/or metastasis of the cancer.

The term “one or more” has the same meaning as “at least one”.

The term “patient” means an animal, such as a mammal (e.g., a humanbeing, and preferably a human being).

The term sequentially-represents (1) administration of one component ofthe method ((a) compound of the invention, or (b) chemotherapeuticagent, signal transduction inhibitor and/or radiation therapy) followedby administration of the other component or components. Afteradministration of one component, the next component can be administeredsubstantially immediately after the first component, or the nextcomponent can be administered after an effective time period followingthe administration of the first component. The effective time period isthe amount of time given for realization of maximum benefit from theadministration of the first component.

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules. This physical associationinvolves varying degrees of ionic and covalent bonding, includinghydrogen bonding. In certain instances the solvate will be capable ofisolation, for example when one or more solvent molecules areincorporated in the crystal lattice of the crystalline solid. “Solvate”encompasses both solution-phase and isolatable solvates. Non-limitingexamples of suitable solvates include ethanolates, methanolates, and thelike; “hydrate” is a solvate wherein the solvent molecule is H₂O.

The term “fused” with reference to, for example, two fused rings meansthat the two rings have two atoms in common.

The term “monocyclic”, as used to describe a ring, means the ring is asingle ring (i.e., the ring is not a fused ring). Thus, for example, a“monocyclic heteroaryl ring” means a single heteroaryl ring.

The term “administration” and variants thereof (e.g., “administering” acompound) in reference to a compound of the invention means introducingthe compound or a prodrug of the compound into the system of the animalin need of treatment. When a compound of the invention or prodrugthereof is provided in combination with one or more other active agents(e.g., a cytotoxic agent, etc.), “administration” and its variants areeach understood to include concurrent and sequential introduction of thecompound or prodrug thereof and other agents.

As used herein, unless otherwise specified, the terms below have themeanings indicated, and unless otherwise specified, the definitions ofeach term (i.e., moiety or substituent) apply when that term is usedindividually or as a component of another term (e.g., the definition ofaryl is the same for aryl and for the aryl portion ofarylheterocycloalkyl, and the like).

The term “alkenyl” means an aliphatic hydrocarbon group (chain)comprising at least one carbon to carbon double bond, wherein the chaincan be straight or branched, and wherein said group comprises about 2 toabout 15 carbon atoms. Preferred alkenyl groups comprise about 2 toabout 12 carbon atoms in the chain; and more preferably about 2 to about6 carbon atoms in the chain; branched means that one or more lower alkylgroups, such as methyl, ethyl or propyl, or alkenyl groups are attachedto a linear alkenyl chain; non-limiting examples of suitable alkenylgroups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl,n-pentenyl, octenyl and decenyl.

The term “alkoxy” means an alkyl-O— group (i.e., the bond to the parentmoiety is through the ether oxygen) in which the alkyl group is asdefined below. Non-limiting examples of suitable alkoxy groups includemethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptoxy.

The term “alkyl” (including the alkyl portions of other moieties, suchas alkoxy) means an aliphatic hydrocarbon group (chain) that can bestraight or branched wherein said group comprises about 1 to about 20carbon atoms in the chain. In one example said alkyl group comprisesabout 1 to about 12 carbon atoms in the chain, in another example about1 to about 6 carbon atoms in the chain; in another example 1 to about 4carbon atoms in the chain; and in another example 1 to about 2 carbonatoms in the chain. Branched alkyl means that one or more lower alkylgroups, such as methyl, ethyl or propyl, are attached to a linear alkylchain. “Lower alkyl” means a group comprising about 1 to about 6 carbonatoms in the chain, and said chain can be straight or branched.

The term “alkylene” (including the alkylene portions of other moieties,such as -alkylene-aryl) means a chain comprising at least one —(CH₂)—group. Examples of alkylene chains include, but are not limited to:—(CH₂)₁₋₆—, —(CH₂)₁₋₄—, —(CH₂)₁₋₂— and —(CH₂)—.

The term “amino” means an —NH₂ group.

The term “aryl” (sometimes abbreviated “ar”) (including the aryl portionof fused heteroarylaryl and fused arylheterocycloalkyl) means anaromatic monocyclic or multicyclic ring system comprising about 6 toabout 14 carbon atoms, preferably about 6 to about 10 carbon atoms.Non-limiting examples of suitable aryl groups include phenyl andnaphthyl.

The term“arylalkyl” (or aralkyl) means an aryl-alkyl- group (i.e., thebond to the parent moiety is through the alkyl group) wherein the aryland alkyl moieties are as defined above; preferred arylalkyls comprise alower alkyl group; non-limiting examples of suitable aralkyl groupsinclude benzyl, 2-phenethyl and naphthalenylmethyl.

The term “cycloalkyl” means a non-aromatic mono- or multicyclic ringsystem comprising about 3 to about 7 carbon atoms, preferably about 3 toabout 6 carbon atoms. Non-limiting examples of suitable monocycliccycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyland the like. Non-limiting examples of suitable multicyclic cycloalkylsinclude 1-decalin, norbornyl, adamantyl and the like.

The term “halo” means fluoro, chloro, bromo, or iodo groups. Preferredhalos are fluoro, chloro or bromo, and more preferred are fluoro andchloro.

The term “halogen” means fluorine, chlorine, bromine, or iodine.Preferred halogens are fluorine, chlorine and bromine.

The term “heteroaryl” means an aromatic monocyclic or multicyclic ringsystem (e.g., a fused ring system) comprising about 5 to about 14 ringatoms, preferably about 5 to about 10 ring atoms, in which one or moreof the ring atoms is an element other than carbon, for example nitrogen,oxygen or sulfur, alone or in combination. Preferred heteroarylscomprise about 5 to about 6 ring atoms. The prefix aza, oxa or thiabefore the heteroaryl root name means that at least a nitrogen, oxygenor sulfur atom, respectively, is present as a ring atom. A nitrogen atomof a heteroaryl can be optionally oxidized to the corresponding N-oxide.The heteroaryl multicyclic ring system includes two rings fused together(i.e., there are two atoms common to both rings). Examples of theheteroaryl multicyclic ring system include fused heteroarylaryl rings(i.e., a heteroaryl ring fused to an aryl ring), and fusedheteroarylheteroaryl rings (i.e., a heteroaryl ring fused to aheteroaryl ring). Non-limiting examples of suitable heteroaryls includepyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl,isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl,pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl,quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridinyl,imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl,benzimidazolyl, benzothienyl, benzopyrazolyl, quinolinyl, imidazolyl,thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl,imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl,benzothiazolyl, furopyridine

and the like.

The term “heteroarylalkyl” (or heteroaralkyl) means a heteroaryl-alkyl-group (i.e., the bond to the parent moiety is through the alkyl group)in which the heteroaryl and alkyl moieties are as defined above;preferred heteroarylalkyls comprise an alkyl group that is a lower alkylgroup; non-limiting examples of suitable aralkyl groups includepyridyl-CH₂—, pyrimidinyl-CH₂—, imidazolyl-CH₂; pyrazinyl-CH₂—, andthiazolyl-CH₂—.

The term “fused heteroarylaryl” means a monocyclic heteroaryl ring fusedto an aryl ring (i.e., the heteroaryl ring and the aryl ring have twoatoms in common).

The term “fused (substituted heteroarylaryl)” means a monocyclicheteroaryl ring fused to an aryl ring (i.e., the heteroaryl ring and thearyl ring have two atoms in common) wherein one or both rings aresubstituted.

The term “fused heteroarylheteroaryl” means a monocyclic heteroaryl ringfused to a monocyclic heteroaryl ring (i.e., one heteroaryl ring has twoatoms in common with the other heteroaryl ring), and each heteroarylring is independently selected.

The term “substituted fused heteroarylheteroaryl” (or “fused(substituted heteroarylheteroaryl”) means a monocyclic heteroaryl ringfused to a monocyclic heteroaryl ring (i.e., one heteroaryl ring has twoatoms in common with the other heteroaryl ring), wherein one or bothrings are substituted. Each heteroaryl ring is independently selected.

The term “fused arylheteroaryl” means an aryl ring fused to a monocyclicheteroaryl ring (i.e., the aryl ring and the heteroaryl ring have twoatoms in common).

The term “fused (substituted arylheteroaryl)” means an aryl ring fusedto a monocyclic heteroaryl ring (i.e., the aryl ring and the heteroarylring have two atoms in common) wherein one or both rings aresubstituted.

The term “fused heterocycloalkylaryl” means a heterocycloalkyl ringfused to an aryl ring (i.e., the heterocycloalkyl ring and the aryl ringhave two atoms in common).

The term “substituted fused heterocycloalkyaryl” means aheterocycloalkyl ring fused to an aryl ring (i.e., the heterocycloalkylring and the aryl ring have two atoms in common), wherein one or bothrings are substituted.

The term “fused heterocycloalkylheteroaryl” means a heterocycloalkylring fused to a heteroaryl ring (i.e., the heterocycloalkyl ring and theheteroaryl ring have two atoms in common).

The term “substituted fused heterocycloalkylheteroaryl” means aheterocycloalkyl ring fused to a heteroaryl ring (i.e., theheterocycloalkyl ring and the heteroaryl ring have two atoms in common),wherein one or both rings are substituted.

The term “heterocycloalkenyl” (or “heterocyclenyl”) means a non-aromaticmonocyclic or multicyclic ring system comprising about 3 to about 10ring atoms, preferably about 5 to about 10 ring atoms, in which one ormore of the atoms in the ring system is an element other than carbon(for example one or more heteroatoms independently selected from thegroup consisting of nitrogen, oxygen and sulfur atom), and whichcontains at least one carbon-carbon double bond or carbon-nitrogendouble bond; there are no adjacent oxygen and/or sulfur atoms present inthe ring system. Preferred heterocyclenyl rings contain about 5 to about6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl rootname means that at least a nitrogen, oxygen or sulfur atom,respectively, is present as a ring atom. The nitrogen or sulfur atom ofthe heterocyclenyl can be optionally oxidized to the correspondingN-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitablemonocyclic azaheterocyclenyl groups include 1,2,3,4-tetrahydropyridine,1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine,1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl,2-imidazolinyl, 2-pyrazolinyl, and the like. Non-limiting examples ofsuitable oxaheterocyclenyl groups include 3,4-dihydro-2H-pyran,dihydrofuranyl, fluorodihydrofuranyl, and the like. A non-limitingexample of a suitable multicyclic oxaheterocyclenyl group is7-oxabicyclo[2.2.1]heptenyl; non-limiting examples of suitablemonocyclic thiaheterocyclenyl rings include dihydrothiophenyl,dihydrothiopyranyl, and the like.

The term “heterocycloalkyl” (or “heterocyclyl”) means a non-aromaticsaturated monocyclic or multicyclic ring system comprising about 3 toabout 10 ring atoms, preferably about 5 to about 10 ring atoms, in whichone or more of the atoms in the ring system is an element other thancarbon, for example nitrogen, oxygen or sulfur, alone or in combination.There are no adjacent oxygen and/or sulfur atoms present in the ringsystem. Preferred heterocyclyls contain about 5 to about 6 ring atoms.The prefix aza, oxa or thia before the heterocyclyl root name means thatat least a nitrogen, oxygen or sulfur atom respectively is present as aring atom. The nitrogen or sulfur atom of the heterocyclyl can beoptionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclylrings include azetidinyl, piperidyl, pyrrolidinyl, piperazinyl,morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl,1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl,tetrahydrothiopyranyl, and the like. The heterocycloalkyl rings of thisinvention can be “bridged heterocycloalkyl rings. The term “bridgedheterocycloalkyl”” (or “bridged heterocyclyl”) means a heterocycloalkylgroup as defined above having an alkylene chain (generally a 1 or 2carbon alkylene chain, not counting the atoms in the ring to which thealkylene chain is bound) bridging two carbon atoms in the ring.

Any carbon or heteroatom with unsatisfied valences in the text, schemes,examples, structural formulae, and any tables herein is assumed to havethe hydrogen atom or atoms to satisfy the valences. And any one or moreof these hydrogen atoms can be deuterium.

Those skilled the art will appreciate that formulas showing a bond thatdoes not have a substituent at the end of the bond represents a methylgroup. Thus, for example,

is the same moiety as

One or more compounds of the invention may also exist as, or beoptionally converted to, a solvate. Preparation of solvates is generallyknown. Thus, for example, M. Caira et al, J. Pharmaceutical Sci., 93(3),601-611 (2004) describe the preparation of the solvates of theantifungal fluconazole in ethyl acetate as well as from water. Similarpreparations of solvates, hemisolvate, hydrates and the like aredescribed by E. C. van Tonder et al, AAPS PharmSciTech., 5(1), article12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001). Atypical, non-limiting, process involves dissolving the inventivecompound in desired amounts of the desired solvent (organic or water ormixtures thereof) at a higher than ambient temperature, and cooling thesolution at a rate sufficient to form crystals which are then isolatedby standard methods. Analytical techniques such as, for example I. R.spectroscopy, show the presence of the solvent (or water) in thecrystals as a solvate (or hydrate).

The term “pharmaceutical composition” is also intended to encompass boththe bulk composition and individual dosage units comprised of more thanone (e.g., two) pharmaceutically active agents such as, for example, acompound of the present invention and an additional agent selected fromthe lists of the additional agents described herein, along with anypharmaceutically inactive excipients. The bulk composition and eachindividual dosage unit can contain fixed amounts of the afore-said “morethan one pharmaceutically active agents”. The bulk composition ismaterial that has not yet been formed into individual dosage units. Anillustrative dosage unit is an oral dosage unit such as tablets,capsules, pills and the like. Similarly, the herein-described methods oftreating a patient by administering a pharmaceutical composition of thepresent invention is also intended to encompass the administration ofthe afore-said bulk composition and individual dosage units.

The compounds of the present invention may have asymmetric centers,chiral axes, and chiral planes (as described in: E. L. Eliel and S. H.Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York,1994, pages 1119-1190), and occur as racemates, racemic mixtures, and asindividual diastereomers, with all possible isomers and mixturesthereof, including optical isomers, being included in the presentinvention. In addition, the compounds disclosed herein may exist astautomers and both tautomeric forms are intended to be encompassed bythe scope of the invention, even though only one tautomeric structure isdepicted. Also, for example, all keto-enol and imine-enamine forms ofthe compounds are included in the invention.

Tautomeric forms such as, for example, the moieties:

are considered equivalent in certain embodiments of this invention.

Thus, all stereoisomers (for example, geometric isomers, optical isomersand the like) of the present compounds (including those of the salts,solvates and prodrugs of the compounds as well as the salts and solvatesof the prodrugs), such as those which may exist due to asymmetriccarbons on various substituents, including enantiomeric forms (which mayexist even in the absence of asymmetric carbons), rotameric forms,atropisomers, and diastereomeric forms, are contemplated within thescope of this invention. Individual stereoisomers of the compounds ofthe invention may, for example, be substantially free of other isomers,or may be admixed, for example, as racemates or with all other, or otherselected, stereoisomers. The chiral centers of the present invention canhave the S or R configuration as defined by the IUPAC 1974Recommendations. The use of the terms “salt”, “solvate” “prodrug” andthe like, is intended to equally apply to the salt, solvate and prodrugof enantiomers, stereoisomers, rotamers, tautomers, racemates orprodrugs of the inventive compounds.

Diasteromeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diasteromericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of Formula (1) may be atropisomers and areconsidered as part of this invention. Enantiomers can also be separatedby use of chiral HPLC column.

When any variable occurs more than one time in any constituent, itsdefinition on each occurrence is independent at every other occurrence.Also, combinations of substituents and variables are permissible only ifsuch combinations result in stable compounds. Lines drawn into the ringsystems from substituents indicate that the indicated bond may beattached to any of the substitutable ring atoms. If the ring system isbicyclic, it is intended that the bond be attached to any of thesuitable atoms on either ring of the bicyclic moiety.

It is understood that substituents and substitution patterns on thecompounds of the instant invention can be selected by one of ordinaryskill in the art to provide compounds that are chemically stable andthat can be readily synthesized by techniques known in the art, as wellas those methods set forth below, from readily available startingmaterials. If a substituent is itself substituted with more than onegroup, it is understood that these multiple groups may be on the samecarbon or on different carbons, so long as a stable structure results.Also, “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

It is understood that one or more silicon (Si) atoms can be incorporatedinto the compounds of the instant invention in place of one or morecarbon atoms by one of ordinary skill in the art to provide compoundsthat are chemically stable and that can be readily synthesized bytechniques known in the art from readily available starting materials.Carbon and silicon differ in their covalent radius leading todifferences in bond distance and the steric arrangement when comparinganalogous C-element and Si-element bonds. These differences lead tosubtle changes in the size and shape of silicon-containing compoundswhen compared to carbon. One of ordinary skill in the art wouldunderstand that size and shape differences can lead to subtle ordramatic changes in potency, solubility, lack of off target activity,packaging properties, and so on. (Diass, J. O. et al. Organometallics(2006) 5:1188-1198; Showell, G. A. et al. Bioorganic & MedicinalChemistry Letters (2006) 16:2555-2558).

Prodrugs of the compounds of the invention are also contemplated herein.The term “prodrug”, as employed herein, denotes a compound that is adrug precursor which, upon administration to a subject, undergoeschemical conversion by metabolic or chemical processes to yield acompound of formula (1) or a salt and/or solvate thereof. A discussionof prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as NovelDelivery Systems (1987) 14 of the A.C.S. Symposium Series, and inBioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed.,American Pharmaceutical Association and Pergamon Press, both of whichare incorporated herein by reference thereto.

This invention also includes the compounds of this invention in isolatedand purified form.

Polymorphic forms of the compounds of formula (1), and of the salts,solvates and prodrugs of the compounds of formula (1), are intended tobe included in the present invention.

The pharmaceutically acceptable salts of the instant compounds can besynthesized from the compounds of this invention which contain a basicor acidic moiety by conventional chemical methods. Generally, the saltsof the basic compounds are prepared either by ion exchangechromatography or by reacting the free base with stoichiometric amountsor with an excess of the desired salt-forming inorganic or organic acidin a suitable solvent or various combinations of solvents. Similarly,the salts of the acidic compounds are formed by reactions with theappropriate inorganic or organic base.

Thus, pharmaceutically acceptable salts of the compounds of thisinvention include the conventional non-toxic salts of the compounds ofthis invention as formed by reacting a basic instant compound with aninorganic or organic acid. For example, conventional non-toxic saltsinclude those derived from inorganic acids such as hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, aswell as salts prepared from organic acids such as acetic, propionic,succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic,pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic,methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic(TFA) and the like.

When the compound of the present invention is acidic, suitable“pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic bases including inorganic basesand organic bases. Salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc and the like. Particularlypreferred are the ammonium, calcium, magnesium, potassium and sodiumsalts. Salts derived from pharmaceutically acceptable organic non-toxicbases include salts of primary, secondary and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as arginine, betainecaffeine, choline, N,N¹-dibenzylethylenediamine, diethylamin,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylaminetripropylamine, tromethamine and the like.

The preparation of the pharmaceutically acceptable salts described aboveand other typical pharmaceutically acceptable salts is more fullydescribed by Berg et al., “Pharmaceutical Salts,” J. Pharm. Sci.,1977:66:1-19.

It will also be noted that the compounds of the present invention arepotentially internal salts or zwitterions, since under physiologicalconditions a deprotonated acidic moiety in the compound, such as acarboxyl group, may be anionic, and this electronic charge might then bebalanced off internally against the cationic charge of a protonated oralkylated basic moiety, such as a quaternary nitrogen atom.

All such acid and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

In hetero-atom containing ring systems of this invention, there are nohydroxyl groups on carbon atoms adjacent to a N, O or S, and there areno N or S groups on carbon adjacent to another heteroatom. Thus, forexample, in the ring:

there is no —OH attached directly to carbons marked 2 and 5.

The term “purified”, “in purified form” or “in isolated and purifiedform” for a compound refers to the physical state of said compound afterbeing isolated from a synthetic process or natural source or combinationthereof. Thus, the term “purified”, “in purified form” or “in isolatedand purified form” for a compound refers to the physical state of saidcompound after being obtained from a purification process or processesdescribed herein or well known to the skilled artisan, in sufficientpurity to be characterizable by standard analytical techniques describedherein or well known to the skilled artisan.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in organic Synthesis(1991), Wiley, New York.

The present invention also embraces isotopically-labelled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, and¹²³I, respectively.

Certain isotopically-labelled compounds of formula (1) (e.g., thoselabeled with ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Certain isotopically-labelled compounds of Formula (1)can be useful for medical imaging purposes. E.g., those labeled withpositron-emitting isotopes like ¹¹C or ¹⁸F can be useful for applicationin Positron Emission Tomography (PET) and those labeled with gamma rayemitting isotopes like ¹²³I can be useful for application in Singlephoton emission computed tomography (SPECT). Further, substitution withheavier isotopes such as deuterium (i.e., ²H) may afford certaintherapeutic advantages resulting from greater metabolic stability (e.g.,increased in vivo half-life or reduced dosage requirements) and hencemay be preferred in some circumstances. Isotopically labeled compoundsof Formula (I), in particular those containing isotopes with longer halflives (T½>1 day), can generally be prepared by following proceduresanalogous to those disclosed in the Schemes and/or in the Examplesherein below, by substituting an appropriate isotopically labeledreagent for a non-isotopically labeled reagent.

This invention provides compounds of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

Q (in Ring A) is selected from the group consisting of: —(CR³)— and N;

X (in Ring B) is selected from the group consisting of: NH and N—O;

the dashed line ( - - - ) between Y and Z in Ring B represents anoptional bond;

when the optional bond is present between Y and Z (i.e., there is adouble bond between Y and Z) then Y is ═C(R⁴)—, and Z is ═C(R⁵)—;

when the optional bond between Y and Z is absent (i.e., there is asingle bond between Y and Z) then Y is selected from the groupconsisting of: —C(R⁴R⁶)— and —N(R⁹)—, and Z is selected from the groupconsisting of: —C(═O)—, —C(R⁷R⁸)— and —C(R⁷R⁸)—C(R⁷R⁸)— wherein each R⁷and each R⁸ is independently selected;

R¹ is selected from the group consisting of: H, halo, —CF₃, —CN,—NR¹²R¹³, —OR¹⁰, —O—(R¹⁰)—O—R¹⁰, —O—R¹⁰—OH, —O—R¹¹, (C₁-C₆)alkyl,substituted (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₃-C₇)cycloalkyl, substituted(C₃-C₇)cycloalkyl, heteroaryl, substituted heteroaryl, heterocycloalkyl,substituted heterocycloalkyl, heterocycloalkenyl-, substitutedheterocycloalkenyl, —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl, (C₆-C₁₄)aryl,substituted (C₆-C₁₄)aryl, —C(O)NH(C₁-C₆)alkyl, —C(O)N((C₁-C₆)alkyl)₂wherein each alkyl is independently selected,—C(O)—(C₁-C₆)alkyl-C(O)—(C₁-C₆)alkyl, —(C₁-C₄)alkyl-C(O)—O—(C₁-C₄)alkyl,—N((C₁-C₆)alkyl)-S(O)₂—(C₁-C₆)alkyl,—N((C₁-C₆)alkyl)-(C₁-C₆)alkyl-O—(C₁-C₆)alkyl, —C(O)NH—(C₁-C₂)alkyl-fusedheteroarylheteroaryl, —C(O)NH—(C₁-C₂)alkyl-(substituted fusedheteroarylheteroaryl), fused arylheterocycloalkyl, substituted fusedarylheterocycloalkyl, —C(O)NH—(C₁-C₂)alkyl-(C₃-C₆)cycloalkyl-N(R⁶)₂,—C(O)NH—(C₁-C₂)alkyl-(substituted (C₃-C₆)cycloalkyl)-N(R⁶)₂,—C(O)NH—(C₁-C₂)alkylheterocycloalkyl, —C(O)NH—(C₁-C₂)alkyl(substitutedheterocycloalkyl), —C(O)NH—(C₁-C₂)alkylheteroaryl,—C(O)NH—(C₁-C₂)alkyl(substituted heteroaryl),—C(O)NH—(C₁-C₆)alkyl-(C₃-C₆)cycloalkyl,—C(O)NH—(C₁-C₆)alkyl-(substituted (C₃-C₆)cycloalkyl),—C(O)NH—(C₁-C₆)alkyl-O—(C₁-C₆)alkyl,—C(O)NH—(C₁-C₆)alkylheterocycloalkyl, —C(O)NH—(C₁-C₆)alkyl(substitutedheterocycloalkyl), —C(O)-heterocycloalkyl-S—(C₁-C₆)alkyl, —C(O)—(substituted heterocycloalkyl-S—(C₁-C₆)alkyl, —C(O)-heterocycloalkyl,—C(O)-(substituted heterocycloalkyl), fused arylheteroaryl, fused(substituted arylheteroaryl), fused heteroarylheteroaryl, fused(substituted heteroarylheteroaryl), fused heterocycloalkylheteroaryl,substituted fused heterocycloalkylheteroaryl,—(C₁-C₄)alkyl-S(O)₂—(C₁-C₆)alkyl, and —(C₁-C₄)alkyl-NH—(C₁-C₆)alkyl;

and wherein said substituted R¹ groups, other than said substituted(C₁-C₆)alkyl, are substituted with 1 to 3 substituents independentlyselected from the group consisting of: —(C₁-C₆)alkyl, halo, CN, —OH,—OR¹⁰, —CF₃, ═O, —NH₂, —NH(C₁-C₆)alkyl, —S(O)₂(C₁-C₆)alkyl,—(C₃-C₆)cycloalkyl, —((C₁-C₆)alkyl)OH,—(C₃-C₆)cycloalkyl-S—(C₃-C₆)cycloalkyl, —N((C₁-C₆)alkyl)₂ wherein eachalkyl is independently selected, —C(O)O—(C₁-C₆)alkyl, —C(O)OH, —OCF₃,—C(O)NH(C₁-C₆)alkyl, heteroaryl, —(C₁-C₆)alkyl)-O—(C₁-C₆)alkyl, fusedheteroarylaryl-, heterocycloalkyl, and heterocycloalkenyl;

and wherein said substituted (C₁-C₆)alkyl R¹ group is substituted with 1to 3 substituents independently selected from the group consisting of:—(C₁-C₆)alkoxy, halo, CN, —OH, ═O, —CF₃, —NH₂, —NH(C₁-C₆)alkyl,—S(O)₂(C₁-C₆)alkyl, fused heteroarylaryl-, heterocycloalkyl, andheterocycloalkenyl;

and wherein the alkyl moieties of the R¹ groups, other than (C₁-C₆)alkyland substituted (C₁-C₆)alkyl, are optionally substituted with 1 to 3substituents independently selected from the group consisting of:(C₁-C₆)alkoxy, halo, CN, —OH, ═O, —CF₃, —NH₂, —NH(C₁-C₆)alkyl,—S(O)₂(C₁-C₆)alkyl, fused heteroarylaryl-, heterocycloalkyl, andheterocycloalkenyl;

and wherein said heteroaryl moiety of said R¹ groups is a 5-10 memberedring comprising 1-3 heteroatoms independently selected from the groupconsisting of: N, O and S, and wherein the remaining ring atoms arecarbon (and wherein said heteroaryl definition applies to the heteroarylmoieties in the R¹ fused heteroarylheteroaryl, substituted fusedheteroarylheteroaryl, fused arylheteroaryl, substituted arylheteroaryl,fused heterocycloalkylheteroaryl, substituted fusedheterocycloalkylheteroaryl, and fused heteroarylaryl- groups);

and wherein said heterocycloalkyl moiety of said R¹ groups is a 3-10membered ring comprising 1-3 heteroatoms independently selected from thegroup consisting of: N, O and S, and wherein the remaining ring atomsare carbon (and wherein said heterocycloalkyl definition applies to theheterocycloalkyl moieties in the R¹ fused heterocycloalkylheteroaryl andsubstituted fused heterocycloalkylheteroaryl groups);

and wherein said heterocycloalkenyl moiety of said R¹ groups is a 3-10membered ring comprising 1-2 double bonds, and 1-3 heteroatomsindependently selected from the group consisting of: N, O and S, and theremaining ring atoms are carbon;

and wherein said fused heteroarylheteroaryl moiety of said R¹ groups isa heteroaryl, as defined above, fused to a heteroaryl, as defined above,such that there are two ring atoms in common with each heteroaryl, andwherein the total ring atoms are 8-11, and wherein said fused ringcomprises 1-4 heteroatoms independently selected from the groupconsisting of: O, N and S, and wherein the remaining ring atoms arecarbon;

and wherein said fused heterocycloalkylheteroaryl moiety of said R¹groups comprises a heteroaryl, as defined above, fused to aheterocycloalkyl, as defined above, such that there are two ring atomsin common with the heterocycloalkyl and heteroaryl, wherein saidheterocycloalkyl is bound to the rest of the molecule, and wherein saidheterocycloalkyl moiety comprises 1-3 heteroatoms independently selectedfrom the group consisting of: N, O and S, and wherein said heteroarylmoiety comprises 1-3 heteroatoms independently selected from the groupconsisting of: N, S, and O;

and wherein said fused arylheteroaryl moiety of said R¹ groups comprisesa C₆-C₁₀ aryl fused to a heteroaryl, as defined above, wherein the aryland the heteroaryl have 2 ring atoms in common;

R² is selected from the group consisting of: H, halo, —NH₂, —OH and—(C₁-C₃)alkyl;

R³ is selected from the group consisting of: H, halo, (C₁-C₆alkyl), and(C₁-C₆alkyl) substituted with 1-2 —OH groups, —(C₃-C₆ cycloalkyl),—(C₁-C₆alkyl)-O—(C₁-C₆alkyl), —(C₁-C₆alkyl)-N(C₁-C₆alkyl)₂ wherein eachalkyl is independently selected, and —(C₁-C₆alkyl)-heterocycloalkyl(wherein said heterocycloalkyl is as defined above for R¹);

R⁴ is selected from the group consisting of: H, halo,(C₆-C₁₄)aryl(C₁-C₆)-alkyl-, substituted (C₆-C₁₄)aryl(C₁-C₆)alkyl-,heteroaryl, substituted heteroaryl, heteroaryl(C₁-C₆)alkyl-, substitutedheteroaryl(C₁-C₆)alkyl-, fused (C₃-C₇)cycloalkyl(C₆-C₁₄)aryl,substituted fused (C₃-C₇)cycloalkyl(C₆-C₁₄)aryl, fusedheterocycloalkyl(C₆-C₁₄)aryl, substituted and fusedheterocycloalkyl(C₆-C₁₄)aryl; wherein said substituted R⁴ moieties aresubstituted with 1-3 substitutents independently selected from the groupconsisting of: halo, (C₁-C₆)alkyl, and (C₁-C₆)alkyl-O—(C₁-C₆)alkyl; andwherein said heteroaryl moiety and said heterocycloalkyl moiety is asdefined above in R¹;

each R⁶, R⁷, and R⁸ is independently selected from the group consistingof: H, halo, (C₆-C₁₄)aryl(C₁-C₆)-alkyl-, substituted(C₆-C₁₄)aryl(C₁-C₆)alkyl-, heteroaryl, substituted heteroaryl,heteroaryl(C₁-C₆)alkyl-, substituted heteroaryl(C₁-C₆)alkyl-, fused(C₃-C₇)cycloalkyl(C₆-C₁₄)aryl, substituted fused(C₃-C₇)cycloalkyl(C₆-C₁₄)aryl, fused heterocycloalkyl(C₆-C₁₄)aryl, andsubstituted fused heterocycloalkyl(C₆-C₁₄)aryl; wherein said substitutedR⁶, R⁷, R⁸ moieties are substituted with 1-3 substitutents independentlyselected from the group consisting of: halo, (C₁-C₆)alkyl, and(C₁-C₆)alkyl-O—(C₁-C₆)alkyl; and wherein said heteroaryl moiety and saidheterocycloalkyl moiety is as defined above in R¹;

R⁹ is selected from the group consisting of: H,(C₆-C₁₀)aryl(C₁-C₆)alkyl, substituted (C₆-C₁₄)aryl(C₁-C₆)alkyl-,heteroaryl, substituted heteroaryl, heteroaryl(C₁-C₆)alkyl-, substitutedheteroaryl(C₁-C₆)alkyl-, fused (C₃-C₇)cycloalkyl(C₆-C₁₄)aryl,substituted fused (C₃-C₇)cycloalkyl(C₆-C₁₄)aryl, fusedheterocycloalkyl(C₆-C₁₄)aryl, and substituted fusedheterocycloalkyl(C₆-C₁₄)aryl; wherein said substituted R⁹ moieties aresubstituted with 1-3 substitutents independently selected from the groupconsisting of: halo, OH, CN, CF₃, (C₁-C₆)alkyl, and(C₁-C₆)alkyl-O—(C₁-C₆)alkyl; and wherein said heteroaryl moiety and saidheterocycloalkyl moiety is as defined above for R¹;

each R¹⁰ is independently selected from the group consisting of:C₁-C₆alkyl and heterocycloalkyl having 5-6 ring atoms comprising 1-2oxygen atoms;

R¹¹ is a 4-7 membered heterocycloalkyl ring comprising 1-3 heteroatomsindependently selected from the group consisting of: O, S and N; and

R¹² and R¹³ are independently selected from the group consisting of: H,(C₁-C₆)alkyl, —C(O)OR¹⁰, and —C(O)R¹⁰, said alkyl group optionallysubstituted with 1-4 halo substitutents independently selected from thegroup consisting of: halo.

Embodiments of this invention include compounds wherein the R¹heteroaryl moiety is a 5-10 membered ring comprising 1-3 heteroatomsindependently selected from the group consisting of: N, O and S, andwherein the remaining ring atoms are carbon. Embodiments of thisinvention also include compounds in these embodiments include compoundswherein the R¹ heteroaryl moiety is a 5-7 membered ring comprising 1-3heteroatoms independently selected from the group consisting of: N, Oand S, and wherein the remaining ring atoms are carbon. Embodiments ofthis invention also include compounds wherein the R¹ heteroaryl moietyis a 5-6 membered ring comprising 1-3 heteroatoms independently selectedfrom the group consisting of: N, O and S, and wherein the remaining ringatoms are carbon. Embodiments of this invention include compoundswherein the definitions of the R¹ heteroaryl moiety in this paragraphapplies to the heteroaryl moieties in the R¹ fused heteroarylheteroaryl,substituted fused heteroarylheteroaryl, fused arylheteroaryl,substituted arylheteroaryl, fused heterocycloalkylheteroaryl,substituted fused heterocycloalkylheteroaryl, and fused heteroarylaryl-groups.

Embodiments of this invention include compounds wherein the R¹heterocycloalkyl moiety is a 3-10 membered ring comprising 1-3heteroatoms independently selected from the group consisting of: N, Oand S, and wherein the remaining ring atoms are carbon. Embodiments ofthis invention include compounds wherein the R¹ heterocycloalkyl moietyis a 4-8 membered ring comprising 1-3 heteroatoms independently selectedfrom the group consisting of: N, O and S, and wherein the remaining ringatoms are carbon. Embodiments of this invention include compoundswherein the definitions of the R¹ heterocycloalkyl moiety in thisparagraph applies to the heterocycloalkyl moieties in the R¹ fusedheterocycloalkylheteroaryl and substituted fusedheterocycloalkylheteroaryl groups.

Embodiments of this invention include compounds wherein the R¹heterocycloalkenyl moiety is a 3-10 membered ring comprising 1-2 doublebonds (e.g., one double bond), and 1-3 heteroatoms independentlyselected from the group consisting of: N, O and S, and the remainingring atoms are carbon. Embodiments of this invention include compoundswherein the R¹ heterocycloalkenyl moiety is a 4-8 membered ringcomprising 1-2 double bonds (e.g., one double bond), and 1-3 heteroatomsindependently selected from the group consisting of: N, O and S, and theremaining ring atoms are carbon. Embodiments of this invention includecompounds wherein the R¹ heterocycloalkenyl moiety is a 4-6 memberedring comprising 1-2 double bonds (e.g., one double bond), and 1-3heteroatoms independently selected from the group consisting of: N, Oand S, and the remaining ring atoms are carbon.

Embodiments of this invention include compounds wherein the R¹ fusedheteroarylheteroaryl is a heteroaryl fused to a heteroaryl such thatthere are two ring atoms in common with each heteroaryl, and wherein thetotal ring atoms are 8-11, and wherein said fused ring comprises 1-4heteroatoms independently selected from the group consisting of: O, Nand S, and wherein the remaining ring atoms are carbon. In theseembodiments each heteroaryl is independently selected from the groupconsisting of: 5-10 membered heteroaryl rings comprising 1-3 heteroatomsindependently selected from the group consisting of: N, O and S, andwherein the remaining ring atoms are carbon. Or, in these embodimentseach heteroaryl is independently selected from the group consisting of:5-7 membered heteroaryl rings comprising 1-3 heteroatoms independentlyselected from the group consisting of: N, O and S, and wherein theremaining ring atoms are carbon. Or, in these embodiments eachheteroaryl is independently selected from the group consisting of: 5-6membered heteroaryl rings comprising 1-3 heteroatoms independentlyselected from the group consisting of: N, O and S, and wherein theremaining ring atoms are carbon.

Embodiments of this invention include compounds wherein the R¹ fusedheterocycloalkylheteroaryl comprises a heteroaryl, as defined above,fused to a heterocycloalkyl, as defined above, such that there are tworing atoms in common with the heterocycloalkyl and heteroaryl.Embodiments of this invention also include compounds wherein the R¹fused heterocycloalkylheteroaryl comprises a 5-6 membered heteroaryl, asdefined above, fused to a 4-8 membered heterocycloalkyl, as definedabove, such that there are two ring atoms in common with theheterocycloalkyl and heteroaryl. Embodiments of this invention alsoinclude compounds wherein the R¹ fused heterocycloalkylheteroarylcomprises a 5-6 membered heteroaryl ring, as defined above, wherein theheteroatoms in said heteroaryl are independently selected from the groupconsisting of N and S, and wherein said heteroaryl is fused to a 4-8membered heterocycloalkyl, as defined above, wherein the heteroatom, orheteroatoms, in said heterocycloalkyl are nitrogen, such that there aretwo ring atoms in common with the heterocycloalkyl and heteroaryl.

Embodiments of this invention include compounds wherein the R¹ fusedarylheteroaryl moiety comprises a C₆-C₁₀ aryl (e.g., phenyl) fused to aheteroaryl, as defined above, wherein the aryl and the heteroaryl have 2ring atoms in common. Embodiments of this invention also includecompounds wherein the R¹ fused arylheteroaryl moiety comprises a phenylfused to a heteroaryl, as defined above, wherein the phenyl and theheteroaryl have 2 ring atoms in common.

Embodiments of this invention include compounds wherein the R¹ fusedheterocycloalkylaryl moiety is a C₆-C₁₀ aryl fused to aheterocycloalkyl, as defined above. In one embodiment the R¹ moiety is aphenyl fused to heterocycloalkyl. Examples of the heterocycloalkylmoiety in these embodiments include 5-6 membered rings comprising 1-2heteroatoms, such as for example 6 membered heterocycloalkyl ringscomprising 1-2 heteroatoms, and in other examples a 6 membered ringcomprising 2 heteroatoms, and in other examples a 6 membered ringcomprising two oxygen atoms.

In one embodiment the R¹ halo moiety is I. In one embodiment, when theR¹ groups other than (C₁-C₆)alkyl are substituted with halo, said halois F. In one embodiment, when the R¹ groups other than (C₁-C₆)alkyl aresubstituted with halo, said halo is Cl. In one embodiment, when the R¹groups other than (C₁-C₆)alkyl are substituted with —OR¹⁰ said —OR¹⁰ is(C₁-C₆)alkoxy. In one embodiment the R¹ heteroaryl moiety is a 5-7membered ring. In one embodiment the R¹ heteroaryl moiety is a 5-6membered ring. In one embodiment the R¹ heterocycloalkyl moiety is a 4-8membered ring. In one embodiment the R¹ heterocycloalkenyl moiety hasone double bond. In one embodiment the R¹ heterocycloalkenyl moiety is a4-8 membered ring. In one embodiment the R¹ heterocycloalkenyl moiety isa 4-6 membered ring. In one embodiment the R¹ fusedheterocycloalkylheteroaryl moiety comprises a 5-6 membered heteroarylfused to a 4-8 membered heterocycloalkyl. In one embodiment the R¹ fusedheterocycloalkylheteroaryl moiety comprises a 5-6 membered heteroaryl,fused to a 4-8 membered heterocycloalkyl, wherein said heterocycloalkylcomprises 1-3 nitrogen atoms, and wherein said heteroaryl comprises 1-3heteroatoms independently selected from the group consisting of N and S.In one embodiment the R¹ arylheteroaryl moiety is a phenyl fused to aheteroaryl.

In one embodiment the R³ (C₁-C₆alkyl) substituted with 1-2 —OH groupsmoiety is —(C₁-C₆alkyl)-OH, and in another embodiment —CH₂OH.

In one embodiment the R⁴ halo moiety is Br. In one embodiment, when theR⁴ moiety is substituted with halo, said halo is F. In one embodiment,when the R⁴ moiety is substituted with (C₁-C₆)alkyl-O—(C₁-C₆)alkyl, said(C₁-C₆)alkyl-O—(C₁-C₆)alkyl is (C₁-C₂)alkyl-O—(C₁-C₂)alkyl.

In one embodiment the R⁶, R⁷, and R⁸ halo moiety is Br.

In one embodiment, when the R⁶, R⁷, and R⁸ moieties are substituted withhalo, said halo is F. In one embodiment, when the R⁶, R⁷, and R⁸moieties are substituted with (C₁-C₆)alkyl-O—(C₁-C₆)alkyl, said(C₁-C₆)alkyl-O—(C₁-C₆)alkyl is (C₁-C₂)alkyl-O—(C₁-C₂)alkyl.

In one embodiment, when the R⁹ moiety is substituted with halo, saidhalo is F. In another embodiment, when the R⁹ moiety is substituted with(C₁-C₆)alkyl-O—(C₁-C₆)alkyl, said (C₁-C₆)alkyl-O—(C₁-C₆)alkyl is(C₁-C₂)alkyl-O—(C₁-C₂)alkyl.

In one embodiment the heteroatoms in said R¹¹ heterocycloalkyl ring areoxygen.

In one embodiment, when said (C₁-C₆)alkyl moiety of said R¹² or R¹³moiety is substituted with halo, said halo is F.

In one embodiment Q is —(CR³)—.

In another embodiment Q is N.

The following embodiments are numbered for ease of reference.

In Embodiment (1) the (C₆-C₁₄)aryl moities in formula (I) are phenyl.

In Embodiment (2) X is N. In Embodiment (3) X is N—O.

In Embodiment (4) the optional bond is present (i.e., there is a doublebond between Y and Z) and Y is ═C(R⁴)— and Z is ═C(R⁵)—.

In Embodiment (5) the optional bond is absent (i.e., there is a singlebond between Y and Z) and Y is —C(R⁴R⁶)— and Z is —C(R⁷R⁸)—.

In Embodiment (6) the optional bond is absent (i.e., there is a singlebond between Y and Z) Y is —C(R⁴R⁶)— wherein R⁶ is H, and Z is —C(R⁷R⁸)—wherein R⁷ and R⁸ are each H.

In Embodiment (7) the optional bond is absent (i.e., there is a singlebond between Y and Z) and Y is —C(R⁴R⁶)— and Z is —C(R⁷R⁸)—C(R⁷R⁸)—.

In Embodiment (8) the optional bond is absent (i.e., there is a singlebond between Y and Z), Y is —C(R⁴R⁶)— wherein R⁶ is H, and Z is—C(R⁷R⁸)—C(R⁷R⁸)— wherein each R⁷ and each R⁸ is H.

In Embodiment (9) the optional bond is absent (i.e., there is a singlebond between Y and Z), and Z is —(C═O)—.

In Embodiment (10) the optional bond is absent (i.e., there is a singlebond between Y and Z), Y is —C(R⁴R⁶)— wherein R⁶ is H, and Z is —(C═O)—.

In Embodiment (11) the optional bond is absent (i.e., there is a singlebond between Y and Z) and Y is —N(R⁹)— and Z is —C(R⁷R⁸)—.

In Embodiment (12) the optional bond is absent (i.e., there is a singlebond between Y and Z), Y is —N(R⁹)— and Z is —C(R⁷R⁸)— wherein R⁷ and R⁸are each H.

In Embodiment (13) the optional bond is absent (i.e., there is a singlebond between Y and Z), Y is —N(R⁹)— and Z is —C(R⁷R⁸)—C(R⁷R⁸)—.

In Embodiment (14) the optional bond is absent (i.e., there is a singlebond between Y and Z), Y is —N(R⁹)— and Z is —C(R⁷R⁸)—C(R⁷R⁸)— whereineach R⁷ and R⁸ is H.

In Embodiment (15) the optional bond is absent (i.e., there is a singlebond between Y and Z), Y is —N(R⁹)— and Z is —C(═O)—.

In Embodiment (16) Ring B is selected from the group consisting of:

In Embodiment (17) Ring B is selected from the group consisting of:

In Embodiment (18) Ring B is selected from the group consisting of:(a2), (b3), (c2), (d2), (e2) and (e3).

In Embodiment (19) R² is H.

In Embodiment (20) R² is halo.

In Embodiment (21) Q is —(CR³)— and R³ is H.

In Embodiment (22) Q is —(CR³)— and R³ is —CH₂OH.

In Embodiment (23) R⁵ is H.

In Embodiment (24) Ring B is (a2). In Embodiment (25) Ring B is (a2) andR⁵ is H.

In Embodiment (26) Ring B is (a3). In Embodiment (27) Ring B is (a3) andR⁵ is H.

In Embodiment (28) Ring B is (b2). In Embodiment (29) Ring B is (b2) andR⁶ is H. In Embodiment (30) Ring B is (b2), R⁶ is H, R⁷ is H, and R⁸ isH.

In Embodiment (31) Ring B is (b3). In Embodiment (32) Ring B is (b3) andR⁶ is H. In Embodiment (33) Ring B is (b3), R⁶ is H, R⁷ is H, and R⁸ isH.

In Embodiment (34) Ring B is (c2). In Embodiment (35) B is (c2) and R⁶is H. In Embodiment (36) Ring B is (c2), R⁶ is H, each R⁷ is H, and eachR⁸ is H.

In Embodiment (37) Ring B is (c3). In Embodiment (38) Ring B is (c3) andR⁶ is H. In Embodiment (39) Ring B is (c3), R⁶ is H, each R⁷ is H, andeach R⁸ is H.

In Embodiment (40) Ring B is (d2). In Embodiment (41) Ring B is (d2) andR⁷ is H, and R⁸ is H.

In Embodiment (42) Ring B is (d3). In Embodiment (43) Ring B is (d3) andR⁷ is H, and R⁸ is H.

In Embodiment (44) Ring B is (e2). In Embodiment (45) Ring B is (e2),each R⁷ is H, and each R⁸ is H.

In Embodiment (46) Ring B is (e3). In Embodiment (47) Ring B is (e3),each R⁷ is H, and each R⁸ is H.

In Embodiment (48) R¹ is selected from the group consisting of: H, halo,—NR¹²R¹³, —OR¹⁰, —O—(R¹⁰)—O—R¹⁰, —O—R¹⁰—OH, (C₃-C₇)cycloalkyl,substituted (C₃-C₇)cycloalkyl, heterocycloalkyl, substitutedheterocycloalkyl, —OR¹¹, heteroaryl, substituted heteroaryl, fusedarylheteroaryl, and fused (substituted arylheteroaryl). In one examplethe (C₃-C₇)cycloalkyl moiety in this embodiment is (C₃-C₆)cycloalkyl,and in another example (C₃-0₅)cycloalkyl. In one example the substituted(C₃-C₇)cycloalkyl moiety in this embodiment is substituted(C₃-C₆)cycloalkyl, and in another example substituted (C₃-C₅)cycloalkyl.

In Embodiment (49) R¹ is selected from the group consisting of: H, halo,—NR¹²R¹³, —OR¹⁰, —O—(R¹⁰)—O—R¹⁰, —O—R¹⁰—OH, (C₃-C₇)cycloalkyl,heterocycloalkyl, substituted heterocycloalkyl, —OR¹¹, heteroaryl,substituted heteroaryl, fused arylheteroaryl, and fused (substitutedarylheteroaryl). In one example the (C₃-C₇)cycloalkyl moiety in thisembodiment is (C₃-C₆)cycloalkyl, and in another example(C₃-C₅)cycloalkyl.

In Embodiment (50) R¹ is selected from the group consisting of: H, I,Br, —NH₂, —NHCH₂CH₃, —NHCH(CH₃)C(F)₃, —NHC(O)OCH₃, —NHC(O)CH₃, —OCH₃,—OCH₂CH₂OCH₃, —OCH₂CH₂OH, —(CH₂)₃—O—CH₃, CH₃CH₂CH₂—, cyclopropyl,CH₃CH═CH—,

In Embodiment (51) R¹ is H. In embodiment (52) R¹ is —NH₂. In embodiment(53) R¹ is CH₃CH₂CH₂—. In embodiment (54) R¹ is CH₃CH═CH—. In embodiment(55) R¹ is —N(H)CH₂CH₃. In Embodiment (56) R¹ is —N(H)CH(CH₃)C(F)₃. InEmbodiment (57) R¹ is —N(H)C(O)OCH₃. In Embodiment (58) R¹ is—N(H)C(O)CH₃. In Embodiment (59) R¹ is —OCH₃. In Embodiment (60) R¹ is—OCH₂CH₂OCH₃. In Embodiment (61) R¹ is —OCH₂CH₂OH. In Embodiment (62) R¹is (f1). In Embodiment (63) R¹ is (f2). In Embodiment (64) R¹ is (f3).In Embodiment (65) R¹ is (f4). In Embodiment (66) R¹ is (f5). InEmbodiment (67) R¹ is (f6). In Embodiment (68) R¹ is (f7). In Embodiment(69) R¹ is (f8). In Embodiment (70) R¹ is (f9). In Embodiment (71) R¹ is(f10). In Embodiment (72) R¹ is (f11). In Embodiment (73) R¹ is (f12).In Embodiment (74) R¹ is (f13). In Embodiment (75) R¹ is (f14). InEmbodiment (76) R¹ is (f15). In Embodiment (77) R¹ is (f16). InEmbodiment (78) R¹ is (f17). In Embodiment (79) R¹ is (f18). InEmbodiment (80) R¹ is (f19). In Embodiment (81) R¹ is (f20). InEmbodiment (82) R¹ is (f21). In Embodiment (83) R¹ is (f22). InEmbodiment (84) R¹ is (f23). In Embodiment (85) R¹ is (f24). InEmbodiment (86) R¹ is (f25). In Embodiment (87) R¹ is (f26). InEmbodiment (88) R¹ is (f27). In Embodiment (89) R¹ is (f28). InEmbodiment (90) R¹ is (f29). In Embodiment (91) R¹ is (f30).

In Embodiment (92) R⁴ is selected from the group consisting of: H, halo,heteroaryl, substituted heteroaryl, pyridyl(C₁-C₂)alkyl-), substitutedpyridyl(C₁-C₂)alkyl-), phenyl-(C₁-C₃)alkyl-), substitutedphenyl-(C₁-C₃)alkyl-), a fused (C₅-C₇)cycloalkylphenyl, a fusedsubstituted (C₅-C₇)cycloalkylphenyl, a fused (5-7membered)-heterocycloalkylphenyl, and a fused substituted (5-7membered)heterocycloalkylphenyl.

In Embodiment (93) R⁴ is selected from the group consisting of: H, Br,

In Embodiment (94) R⁴ is H. In another embodiment R⁴ is Br. InEmbodiment (95) R⁴ is (g1). In Embodiment (96) R⁴ is (g2). In Embodiment(97) R⁴ is (g3). In Embodiment (98) R⁴ is (g4). In Embodiment (99) R⁴ is(g5). In Embodiment (100) R⁴ is (g6). In Embodiment (101) R⁴ is (g7). InEmbodiment (102) R⁴ is (g8). In Embodiment (103) R⁴ is (g9). InEmbodiment (104) t R⁴ is (g10). In Embodiment (105) R⁴ is (g11). InEmbodiment (106) R⁴ is (g12). In Embodiment (107) R⁴ is (g13). InEmbodiment (108) R⁴ is (g14). In Embodiment (109) R⁴ is (g15).

In Embodiment (110) R⁹ is selected from the group consisting of: H,halo, heteroaryl, substituted heteroaryl, pyridyl(C₁-C₂)alkyl-),substituted pyridyl(C₁-C₂)alkyl-), phenyl-(C₁-C₃)alkyl-), substitutedphenyl-(C₁-C₃)alkyl-), a fused (C₅-C₇)cycloalkylphenyl, a fusedsubstituted (C₅-C₇)cycloalkylphenyl), a fused (5-7membered)-heterocycloalkylphenyl), and a fused substituted (5-7membered)heterocycloalkylphenyl.

In Embodiment (111) R⁹ is selected from the group consisting of: H,(g1), (g2), (g3), (g4), (g5), (g6), (g7), (g8), (g9), (g10), (g11),(g12), (g13), (g14), and (g15).

In Embodiment (112) R⁹ is H. In Embodiment (113) R⁹ is (g1). InEmbodiment (114) R⁹ is (g2). In Embodiment (115) R⁹ is (g3). InEmbodiment (116) R⁹ is (g4). In Embodiment (117) R⁹ is (g5). InEmbodiment (118) R⁹ is (g6). In Embodiment (119) R⁹ is (g7). InEmbodiment (120) R⁹ is (g8). In Embodiment (121) R⁹ is (g9). InEmbodiment (122) R⁹ is (g10). In Embodiment (123) R⁹ is (g11). InEmbodiment (124) R⁹ is (g12). In Embodiment (125) R⁹ is (g13). InEmbodiment (126) R⁹ is (g14). In Embodiment (127) R⁹ is (g15).

In Embodiment (113):

(1) R¹ is selected from the group consisting of: H, I, —NH₂, —NHCH₂CH₃,—NHCH(CH₃)C(F)₃, —NHC(O)OCH₃, —NHC(O)CH₃, —OCH₃, —OCH₂CH₂OCH₃,—OCH₂CH₂OH, (f1), (f2), (f3), (f4), (f5), (f6), (f7), (f8), (f9), (f10),(f11), and (f12);

(2) R⁴ is selected from the group consisting of: H, Br, (g1), (g2),(g3), (g4), (g5), (g6), (g7), (g8), (g9), (g10), (g11), (g12), (g13),(g14), and (g15); and

(3) R⁹ is selected from the group consisting of: H, (g1), (g2), (g3),(g4), (g5), (g6), (g7), (g8), (g9), (g10), (g11), (g12), (g13), (g14),and (g15).

In Embodiment (114):

(1) R¹ is selected from the group consisting of: H, I, —NH₂, —NHCH₂CH₃,—NHCH(CH₃)C(F)₃, —NHC(O)OCH₃, —NHC(O)CH₃, —OCH₃, —OCH₂CH₂OCH₃,—OCH₂CH₂OH, (f1), (f2), (f3), (f4), (f5), (f6), (f7), (f8), (f9), (f10),(f11), and (f12);

(2) R² is selected from the group consisting of: H and halo;

(3) R⁴ is selected from the group consisting of: H, Br, (g1), (g2),(g3), (g4), (g5), (g6), (g7), (g8), (g9), (g10), (g11), (g12), (g13),(g14), and (g15); and

(4) R⁵ is H; and

(5) R⁹ is selected from the group consisting of: H, (g1), (g2), (g3),(g4), (g5), (g6), (g7), (g8), (g9), (g10), (g11), (g12), (g13), (g14),and (g15).

In Embodiment (115):

(1) R¹ is selected from the group consisting of: H, I, —NH₂, —NHCH₂CH₃,—NHCH(CH₃)C(F)₃, —NHC(O)OCH₃, —NHC(O)CH₃, —OCH₃, —OCH₂CH₂OCH₃,—OCH₂CH₂OH, (f1), (f2), (f3), (f4), (f5), (f6), (f7), (f8), (f9), (f10),(f11), and (f12);

(2) R² is selected from the group consisting of: H and halo;

(3) Q is —(CR³)— and R³ is H;

(4) R⁴ is selected from the group consisting of: H, Br, (g1), (g2),(g3), (g4), (g5), (g6), (g7), (g8), (g9), (g10), (g11), (g12), (g13),(g14), and (g15); and

(5) R⁵ is H; and

(6) R⁹ is selected from the group consisting of: H, (g1), (g2), (g3),(g4), (g5), (g6), (g7), (g8), (g9), (g10), (g11), (g12), (g13), (g14),and (g15).

In Embodiment (116):

(1) Ring B is selected from the group consisting of: (a2), (a3), (b2),(b3), (c2), (c3), (d2), (d3), (e2), and (e3);

(2) R¹ is selected from the group consisting of: H, I, —NH₂, —NHCH₂CH₃,—NHCH(CH₃)C(F)₃, —NHC(O)OCH₃, —NHC(O)CH₃, —OCH₃, —OCH₂CH₂OCH₃,—OCH₂CH₂OH, (f1), (f2), (f3), (f4), (f5), (f6), (f7), (f8), (f9), (f10),(f11), and (f12);

(3) R² is selected from the group consisting of: H and halo;

(4) Q is —(CR³)— and R³ is H;

(5) R⁴ is selected from the group consisting of: H, Br, (g1), (g2),(g3), (g4), (g5), (g6), (g7), (g8), (g9), (g10), (g11), (g12), (g13),(g14), and (g15);

(6) R⁵ is H; and

(7) R⁹ is selected from the group consisting of: H, (g1), (g2), (g3),(g4), (g5), (g6), (g7), (g8), (g9), (g10), (g11), (g12), (g13), (g14),and (g15).

In Embodiment (117):

(1) Ring B is selected from the group consisting of: (a2), (a3), (b2),(b3), (c2), (c3), (d2), (d3), (e2), and (e3);

(2) R¹ is selected from the group consisting of: H, I, —NH₂, —NHCH₂CH₃,—NHCH(CH₃)C(F)₃, —NHC(O)OCH₃, —NHC(O)CH₃, —OCH₃, —OCH₂CH₂OCH₃,—OCH₂CH₂OH, (f1), (f2), (f3), (f4), (f5), (f6), (f7), (f8), (f9), (f10),(f11), and (f12);

(3) R² is selected from the group consisting of: H and halo;

(4) Q is —(CR³)— and R³ is H;

(5) R⁴ is selected from the group consisting of: H, Br, (g1), (g2),(g3), (g4), (g5), (g6), (g7), (g8), (g9), (g10), (g11), (g12), (g13),(g14), and (g15);

(6) R⁵, R⁶, R⁷, and R⁸ are H; and

(7) R⁹ is selected from the group consisting of: H, (g1), (g2), (g3),(g4), (g5), (g6), (g7), (g8), (g9), (g10), (g11), (g12), (g13), (g14),and (g15).

In Embodiment (118):

(1) Ring B is selected from the group consisting of: (a2), (b3), (c2),(d2), (e2), and (e3);

(2) R¹ is selected from the group consisting of: H, I, —NH₂, —NHCH₂CH₃,—NHCH(CH₃)C(F)₃, —NHC(O)OCH₃, —NHC(O)CH₃, —OCH₃, —OCH₂CH₂OCH₃,—OCH₂CH₂OH, (f1), (f2), (f3), (f4), (f5), (f6), (f7), (f8), (f9), (f10),(f11), and (f12);

(3) R² is selected from the group consisting of: H and halo;

(4) Q is —(CR³)— and R³ is H;

(5) R⁴ is selected from the group consisting of: H, Br, (g1), (g2),(g3), (g4), (g5), (g6), (g7), (g8), (g9), (g10), (g11), (g12), (g13),(g14), and (g15);

(6) R⁵ is H; and

(7) R⁹ is selected from the group consisting of: H, (g1), (g2), (g3),(g4), (g5), (g6), (g7), (g8), (g9), (g10), (g11), (g12), (g13), (g14),and (g15).

In Embodiment (119):

(1) Ring B is selected from the group consisting of: (a2), (b3), (c2),(d2), (e2), and (e3);

(2) R¹ is selected from the group consisting of: H, I, —NH₂, —NHCH₂CH₃,—NHCH(CH₃)C(F)₃, —NHC(O)OCH₃, —NHC(O)CH₃, —OCH₃, —OCH₂CH₂OCH₃,—OCH₂CH₂OH, (f1), (f2), (f3), (f4), (f5), (f6), (f7), (f8), (f9), (f10),(f11), and (f12);

(3) R² is selected from the group consisting of: H and halo;

(4) Q is —(CR³)— and R³ is H;

(5) R⁴ is selected from the group consisting of: H, Br, (g1), (g2),(g3), (g4), (g5), (g6), (g7), (g8), (g9), (g10), (g11), (g12), (g13),(g14), and (g15);

(6) R⁵, R⁶, R⁷, and R⁸ are H; and

(7) R⁹ is selected from the group consisting of: H, (g1), (g2), (g3),(g4), (g5), (g6), (g7), (g8), (g9), (g10), (g11), (g12), (g13), (g14),and (g15).

Other embodiments of this invention are directed to the compounds ofthis invention in the free base form. Thus, other embodiments aredirected to any one of the embodiments above wherein the compound is inthe free base form.

Other embodiments of this invention are directed to pharmaceuticallyacceptable salts of the compounds of this invention. Thus, otherembodiments are directed to any one of the embodiments above wherein thecompound is a pharmaceutically acceptable salt.

Representative compounds of the invention include, but are not limitedto:

Representative compounds of the invention also include thepharmaceutically acceptable salts of compounds (1) to (47).

Compounds of the invention can have chiral centers, and compounds of theinvention can be obtained as a salt (e.g., a formate ortrifluoroacetate). Thus, compounds of the invention include, forexample, the trifluoroacetate salt of compounds (4)-(9), (11)-(15),(17)-(26), (30)-(37), (39)-(41), (43), (44), and (47). The compounds ofthe invention also include, for example, the formate salt of compounds(27), (28) and (29).

In one embodiment the compound is compound (1). In another embodimentthe compound is compound (2). In another embodiment the compound iscompound (3). In another embodiment the compound is compound (4). Inanother embodiment the compound is compound (5). In another embodimentthe compound is compound (6). In another embodiment the compound iscompound (7). In another embodiment the compound is compound (8). Inanother embodiment the compound is compound (9). In another embodimentthe compound is compound (10). In another embodiment the compound iscompound (11). In another embodiment the compound is compound (12). Inanother embodiment the compound is compound (13). In another embodimentthe compound is compound (14). In another embodiment the compound iscompound (15). In another embodiment the compound is compound (16). Inanother embodiment the compound is compound (17). In another embodimentthe compound is compound (18). In another embodiment the compound iscompound (19). In another embodiment the compound is compound (20). Inanother embodiment the compound is compound (21). In another embodimentthe compound is compound (22). In another embodiment the compound iscompound (23). In another embodiment the compound is compound (24). Inanother embodiment the compound is compound (25). In another embodimentthe compound is compound (26). In another embodiment the compound iscompound (27). In another embodiment the compound is compound (28). Inanother embodiment the compound is compound (29). In another embodimentthe compound is compound (30). In another embodiment the compound iscompound (31). In another embodiment the compound is compound (32). Inanother embodiment the compound is compound (33). In another embodimentthe compound is compound (34). In another embodiment the compound iscompound (35). In another embodiment the compound is compound (36). Inanother embodiment the compound is compound (37). In another embodimentthe compound is compound (38). In another embodiment the compound iscompound (39). In another embodiment the compound is compound (40). Inanother embodiment the compound is compound (41). In another embodimentthe compound is compound (42). In another embodiment the compound iscompound (43). In another embodiment the compound is compound (44). Inanother embodiment the compound is compound (45). In another embodimentthe compound is compound (46). In another embodiment the compound iscompound (47).

Other embodiments are directed to a pharmaceutically acceptable salt ofany one of compounds 1 to 47.

In one embodiment of this invention the compounds of formula (I) areselected from the group consisting of the compounds (4), (6), (7), (8),(10), (13)-(15), (17)-(21), (23), (26), (28), (33), (34), (41) and (45),or a pharmaceutically acceptable salt thereof. In one embodiment of thisinvention the compounds of formula (I) are selected from the groupconsisting of the compounds (4), (6), (7), (8), (10), (13)-(15),(17)-(21), (23), (26), (28), (33), (34), and (41), or a pharmaceuticallyacceptable salt thereof.

Another embodiment of this invention is directed to compounds of formula(I) selected from the group consisting of: (4), (6), (7), (10), and(41), or a pharmaceutically acceptable salt thereof.

Another embodiment of this invention is directed to the solvates of thecompounds of formula (I).

Other embodiments of this invention are directed to any one of theembodiments of formula (I) wherein the compound is in pure and isolatedform. Other embodiments of this invention are directed to any one of theembodiments of formula (I) wherein the compound is in pure form. Otherembodiments of this invention are directed to any one of the embodimentsof formula (I) wherein the compound is in isolated form.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of at least one compound(e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) of formula (I), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier. Another embodiment of this invention is directed toa pharmaceutical composition comprising an effective amount of acompound of formula (I), or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of at least one compoundselected from the group consisting of the compounds (1)-(47), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of at least one compoundselected from the group consisting of the compounds (4), (6), (7), (8),(10), (13)-(15), (17)-(21), (23), (26), (28), (33), (34), (41), and (45)or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of at least one compoundselected from the group consisting of the compounds (4), (6), (7), (8),(10), (13)-(15), (17)-(21), (23), (26), (28), (33), (34) and (41), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of at least one compoundselected from the group consisting of the compounds (4), (6), (7), (10),and (41), or a pharmaceutically acceptable salt thereof, apharmaceutically acceptable carrier, and a pharmaceutically acceptablecarrier.

Another embodiment of this invention is directed to a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I),a chemotherapeutic agent, and a pharmaceutically acceptable carrier.

The compounds of the invention are useful in preparing a medicament thatis useful in treating cancer.

The compounds of this invention inhibit the activity of ERK2 Thus, thisinvention further provides a method of inhibiting ERK in mammals,especially humans, by the administration of an effective amount of oneor more (e.g., one) compounds of this invention. The administration ofthe compounds of this invention to patients, to inhibit ERK2, is usefulin the treatment of cancer.

In any of the methods of treating cancer described herein, unless statedotherwise, the methods can optionally include the administration of aneffective amount of one or more (e.g., 1, 2 or 3, or 1 or 2, or 1)chemotherapeutic agents. The chemotherapeutic agents can be administeredcurrently or sequentially with the compounds of this invention. In thetreatment of breast cancer, the compounds of formula (I) can be beadministered in a treatment protocol which also includes theadministration of an effective amount of at least one (e.g., 1-3, or1-2, or 1) antihormonal agent (i.e., the methods of treating breastcancer can include hormonal therapies).

The methods of treating cancer described herein include methods whereina combination of drugs (e.g., compounds, or pharmaceutically activeingredients, or pharmaceutical compositions) are used (e.g., the methodsof treating cancer of this invention include combination therapies).Those skilled in the art will appreciate that the drugs are generallyadministered individually as a pharmaceutical composition. The use of apharmaceutical composition comprising more than one drug is within thescope of this invention.

The methods of treating cancer described herein include methods oftreating cancer that comprise administering a therapeutically effectiveamount of a compound of the instant invention in combination withradiation therapy and/or in combination with a second compound selectedfrom: an estrogen receptor modulator, an androgen receptor modulator, aretinoid receptor modulator, a cytotoxicytostatic agent, anantiproliferative agent, a prenyl-protein transferase inhibitor, anHMG-CoA reductase inhibitor, an HIV protease inhibitor, a reversetranscriptase inhibitor, an angiogenesis inhibitor, PPAR-γ agonists,PPAR-δ agonists, an inhibitor of inherent multidrug resistance, ananti-emetic agent, an agent useful in the treatment of anemia, an agentuseful in the treatment of neutropenia, an immunologic-enhancing drug,an inhibitor of cell proliferation and survival signaling, abisphosphonate, an aromatase inhibitor, an siRNA therapeutic,γ-secretase and/or NOTCH inhibitors, agents that interfere with receptortyrosine kinases (RTKs), an agent that interferes with a cell cyclecheckpoint, and any of the therapeutic agents listed herein.

In any of the methods of treating cancer described herein, unless statedotherwise, the methods can optionally include the administration of aneffective amount of radiation therapy. For radiation therapy,γ-radiation is preferred.

Thus, another embodiment of this invention is directed to a method oftreating cancer in a patient in need of such treatment, said methodcomprising administering an effective amount of a compound of formula(I). Another embodiment of this invention is directed to a method oftreating cancer in a patient in need of such treatment, said methodcomprising administering to said patient an effective amount of acompound of formula (I), and an effective amount of at least one (e.g.,1-3, 1-2, or 1) chemotherapeutic agent.

The compounds, compositions and methods provided herein are useful forthe treatment of cancer. Cancers that may be treated by the compounds,compositions and methods of the invention include, but are not limitedto: (1) Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma,liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; (2)Lung: bronchogenic carcinoma (squamous cell, undifferentiated smallcell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma,chondromatous hamartoma, mesothelioma, non-small cell; (3)Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma,leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma,leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma,glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel(adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma,leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma), colon, colorectal, rectal; (4) Genitourinary tract: kidney(adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, leukemia),bladder and urethra (squamous cell carcinoma, transitional cellcarcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis(seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, lipoma); (5) Liver: hepatoma(hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma; (6) Bone: osteogenicsarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma and giant celltumors; (7) Nervous system: skull (osteoma, hemangioma, granuloma,xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma,gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma,germinoma [pinealoma], glioblastoma multiform, oligodendroglioma,schwannoma, retinoblastoma, congenital tumors), spinal cordneurofibroma, meningioma, glioma, sarcoma); (8) Gynecological: uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),fallopian tubes (carcinoma), breast; (9) Hematologic: blood (myeloidleukemia [acute and chronic], acute lymphoblastic leukemia, chroniclymphocytic leukemia, chronic myelomonocytic (CMML), myeloproliferativediseases, multiple myeloma, myelodysplastic syndrome), Hodgkin'sdisease, non-Hodgkin's lymphoma [malignant lymphoma]; (10) Skin:malignant melanoma, basal cell carcinoma, squamous cell carcinoma,Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma,dermatofibroma, keloids, psoriasis; and (11) Adrenal glands:neuroblastoma. Examples of cancer that may be treated by the compounds,compositions and methods of the invention include thyroid cancer,anaplastic thyroid carcinoma, epidermal cancer, head and neck cancer(e.g., squamous cell cancer of the head and neck), sarcoma,tetracarcinoma, hepatoma and multiple myeloma. Thus, the term “cancerouscell” as provided herein, includes a cell afflicted by any one of theabove-identified conditions.

In the treatment of breast cancer (e.g., postmenopausal andpremenopausal breast cancer, e.g., hormone-dependent breast cancer) thecompound of formula (I) may be used with an effective amount of at leastone antihormonal agent selected from the group consisting of: (a)aromatase inhibitors, (b) antiestrogens, and (c) LHRH analogues; andoptionally an effective amount of at least one chemotherapeutic agent.Examples of aromatase inhibitors include but are not limited to:Anastrozole (e.g., Arimidex), Letrozole (e.g., Femara), Exemestane(Aromasin), Fadrozole and Formestane (e.g., Lentaron). Examples ofantiestrogens include but are not limited to: Tamoxifen (e.g.,Nolvadex), Fulvestrant (e.g., Faslodex), Raloxifene (e.g., Evista), andAcolbifene. Examples of LHRH analogues include but are not limited to:Goserelin (e.g., Zoladex) and Leuprolide (e.g., Leuprolide Acetate, suchas Lupron or Lupron Depot). Examples of chemotherapeutic agents includebut are not limited to: Trastuzumab (e.g., Herceptin), Gefitinib (e.g.,Iressa), Erlotinib (e.g., Erlotinib HCl, such as Tarceva), Bevacizumab(e.g., Avastin), Cetuximab (e.g., Erbitux), and Bortezomib (e.g.,Velcade).

In one embodiment of this invention the cancer treated is colorectalcancer (such as, for example, colon adenocarcinoma and colon adenoma).Thus, another embodiment of this invention is directed to a method oftreating colorectal cancer in a patient in need of such treatment, saidmethod comprising administering an effective of a compound of formula(I) (in one example, a compound selected from the group consisting ofcompounds (1)-(47), or a pharmaceutically acceptable salt thereof, andin another example a compound selected from the group consisting of:compounds (4), (6), (7), (8), (10), (13)-(15), (17)-(21), (23), (26),(28), (33), (34), (41) and (45), or a pharmaceutically acceptable saltthereof, and in another example compounds (4), (6), (7), (8), (10),(13)-(15), (17)-(21), (23), (26), (28), (33), (34) and (41), or apharmaceutically acceptable salt thereof, and in another example acompound selected from the group consisting of compounds (4), (6), (7),(10), and (41), or a pharmaceutically acceptable salt thereof), to saidpatient. Another embodiment of this invention is directed to a method oftreating colorectal cancer in a patient in need of such treatment, saidmethod comprising administering to said patient an effective amount of acompound of formula (I) (in one example, a compound selected from thegroup consisting of compounds (1)-(47), or a pharmaceutically acceptablesalt thereof, and in another example a compound selected from the groupconsisting of: compounds (4), (6), (7), (8), (10), (13)-(15), (17)-(21),(23), (26), (28), (33), (34), (41) and (45), or a pharmaceuticallyacceptable salt thereof, and in another example compounds (4), (6), (7),(8), (10), (13)-(15), (17)-(21), (23), (26), (28), (33), (34) and (41),or a pharmaceutically acceptable salt thereof, and in another example acompound selected from the group consisting of compounds (4), (6), (7),(10), and (41), or a pharmaceutically acceptable salt thereof), and aneffective amount of at least one (e.g., 1-3, or 1-2, or 1)chemotherapeutic agent.

In one embodiment of this invention the cancer treated is melanoma.Thus, another embodiment of this invention is directed to a method oftreating melanoma in a patient in need of such treatment, said methodcomprising administering an effective amount of a compound of formula(I) (in one example, a compound selected from the group consisting ofcompounds (1)-(47), or a pharmaceutically acceptable salt thereof, andin another example a compound selected from the group consisting of:compounds (4), (6), (7), (8), (10), (13)-(15), (17)-(21), (23), (26),(28), (33), (34), (41) and (45), or a pharmaceutically acceptable saltthereof, and in another example compounds (4), (6), (7), (8), (10),(13)-(15), (17)-(21), (23), (26), (28), (33), (34) and (41), or apharmaceutically acceptable salt thereof, and in another example acompound selected from the group consisting of compounds (4), (6), (7),(10), and (41), or a pharmaceutically acceptable salt thereof), to saidpatient. Another embodiment of this invention is directed to a method oftreating melanoma in a patient in need of such treatment, said methodcomprising administering to said patient an effective amount of acompound of formula (I) (in one example, a compound selected from thegroup consisting of compounds (1)-(47), or a pharmaceutically acceptablesalt thereof, and in another example a compound selected from the groupconsisting of: compounds (4), (6), (7), (8), (10), (13)-(15), (17)-(21),(23), (26), (28), (33), (34), (41) and (45), or a pharmaceuticallyacceptable salt thereof, and in another example compounds (4), (6), (7),(8), (10), (13)-(15), (17)-(21), (23), (26), (28), (33), (34) and (41),or a pharmaceutically acceptable salt thereof, and in another example acompound selected from the group consisting of compounds (4), (6), (7),(10), and (41), or a pharmaceutically acceptable salt thereof), or apharmaceutically acceptable salt thereof, and an effective amount of atleast one (e.g., 1-3, or 1-2, or 1) chemotherapeutic agent.

The compounds of the invention are also useful in preparing a medicamentthat is useful in treating cancer.

The compounds of this invention may be administered to mammals,including humans, either alone or, in combination with pharmaceuticallyacceptable carriers, excipients or diluents, in a pharmaceuticalcomposition, according to standard pharmaceutical practice. Thecompounds can be administered orally or parenterally, including theintravenous, intramuscular, intraperitoneal, subcutaneous, rectal andtopical routes of administration.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, microcrystalline cellulose, sodiumcroscarmellose, corn starch, or alginic acid; binding agents, forexample starch, gelatin, polyvinyl-pyrrolidone or acacia, andlubricating agents, for example, magnesium stearate, stearic acid ortalc. The tablets may be uncoated or they may be coated by knowntechniques to mask the unpleasant taste of the drug or delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a watersoluble taste masking material such as hydroxypropylmethyl-cellulose orhydroxypropylcellulose, or a time delay material such as ethylcellulose, cellulose acetate butyrate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with watersoluble carrier such as polyethyleneglycol or an oil medium, for examplepeanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

The pharmaceutical compositions of the invention may also be in the formof an oil-in-water emulsion. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, for example soy bean lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavouring agents, preservatives and antioxidants.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, flavoring and coloring agentsand antioxidant.

The pharmaceutical compositions may be in the form of sterile injectableaqueous solutions. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution and isotonic sodium chloridesolution.

The sterile injectable preparation may also be a sterile injectableoil-in-water microemulsion where the active ingredient is dissolved inthe oily phase. For example, the active ingredient may be firstdissolved in a mixture of soybean oil and lecithin. The oil solutionthen introduced into a water and glycerol mixture and processed to forma microemulsion.

The injectable solutions or microemulsions may be introduced into apatient's blood-stream by local bolus injection. Alternatively, it maybe advantageous to administer the solution or microemulsion in such away as to maintain a constant circulating concentration of the instantcompound. In order to maintain such a constant concentration, acontinuous intravenous delivery device may be utilized. An example ofsuch a device is the Deltec CADD-PLUS™ model 5400 intravenous pump.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension for intramuscular andsubcutaneous administration. This suspension may be formulated accordingto the known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example as a solution in 1,3-butane diol. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose any bland fixed oil may be employed includingsynthetic mono- or diglycerides. In addition, fatty acids such as oleicacid find use in the preparation of injectables.

Compounds of the instant invention may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials include cocoa butter, glycerinatedgelatin, hydrogenated vegetable oils, mixtures of polyethylene glycolsof various molecular weights and fatty acid esters of polyethyleneglycol.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compound of the instant invention are employed.(For purposes of this application, topical application shall includemouth washes and gargles.)

The compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles anddelivery devices, or via transdermal routes, using those forms oftransdermal skin patches well known to those of ordinary skill in theart. To be administered in the form of a transdermal delivery system,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen. Compounds of the presentinvention may also be delivered as a suppository employing bases such ascocoa butter, glycerinated gelatin, hydrogenated vegetable oils,mixtures of polyethylene glycols of various molecular weights and fattyacid esters of polyethylene glycol.

When a composition according to this invention is administered into ahuman subject, the daily dosage will normally be determined by theprescribing physician with the dosage generally varying according to theage, weight, and response of the individual patient, as well as theseverity of the patient's symptoms.

The dosage regimen utilizing the compounds of the instant invention canbe selected in accordance with a variety of factors including type,species, age, weight, sex and the type of cancer being treated; theseverity (i.e., stage) of the cancer to be treated; the route ofadministration; the renal and hepatic function of the patient; and theparticular compound or salt thereof employed. An ordinarily skilledphysician or veterinarian can readily determine and prescribe theeffective amount of the drug required to treat, for example, to prevent,inhibit (fully or partially) or arrest the progress of the disease.Compounds of this invention can be administered in a total daily dose of10 mg to 3000 mg. For example, compounds of the instant invention can beadministered in a total daily dose of up to 3000 mg. Compounds of theinstant invention can be administered once daily (QD), or divided intomultiple daily doses such as twice daily (BID), and three times daily(TID). Compounds of the instant invention can be administered at a totaldaily dosage of up to 3000 mg, e.g., 200 mg, 300 mg, 400 mg, 600 mg, 800mg, 1000 mg, 2000 mg or 3000 mg, which can be administered in one dailydose or can be divided into multiple daily doses as described above.

In addition, the administration can be continuous, i.e., every day, orintermittently. The terms “intermittent” or “intermittently” as usedherein means stopping and starting at either regular or irregularintervals. For example, intermittent administration of a compound of theinstant invention may be administration one to six days per week or itmay mean administration in cycles (e.g. daily administration for two toeight consecutive weeks, then a rest period with no administration forup to one week) or it may mean administration on alternate days. Thecompounds of this invention may be administered discontinuously ratherthan continuously during the treatment cycle. Thus, the compounds ofthis invention may be administered daily for one or more weeks duringthe cycle and discontinued for one or more weeks during the cycle, withthis pattern of administration repeating during the treatment cycle(e.g., administration for a week and then discontinued for a week). Thisdiscontinuous treatment may also be based upon numbers of days ratherthan a full week. The number of days (or weeks) that the compounds ofthis invention are not dosed do not have to equal the number of days (orweeks) wherein the compounds of this invention are dosed. Usually, if adiscontinuous dosing protocol is used, the number of days or weeks thatthe compounds of this invention are dosed is at least equal to orgreater than the number of days or weeks that the compounds of thisinvention are not dosed.

In addition, the compounds of the instant invention may be administeredaccording to any of the schedules described above, consecutively for afew weeks, followed by a rest period. For example, the compounds of theinstant invention may be administered according to any one of theschedules described above from two to eight weeks, followed by a restperiod of one week, or twice daily at a dose of 100-500 mg for three tofive days a week. In another particular embodiment, the compounds of theinstant invention may be administered three times daily for twoconsecutive weeks, followed by one week of rest.

Any one or more of the specific dosages and dosage schedules of thecompounds of the instant invention, may also be applicable to any one ormore of the therapeutic agents to be used in the combination treatment(hereinafter referred to as the “second therapeutic agent”).

Moreover, the specific dosage and dosage schedule of this secondtherapeutic agent can further vary, and the optimal dose, dosingschedule and route of administration will be determined based upon thespecific second therapeutic agent that is being used.

Of course, the route of administration of the compounds of the instantinvention is independent of the route of administration of the secondtherapeutic agent. In an embodiment, the administration for a compoundof the instant invention is oral administration. In another embodiment,the administration for a compound of the instant invention isintravenous administration. Thus, in accordance with these embodiments,a compound of the instant invention is administered orally orintravenously, and the second therapeutic agent can be administeredorally, parenterally, intraperitoneally, intravenously, intraarterially,transdermally, sublingually, intramuscularly, rectally, transbuccally,intranasally, liposomally, via inhalation, vaginally, intraoccularly,via local delivery by catheter or stent, subcutaneously,intraadiposally, intraarticularly, intrathecally, or in a slow releasedosage form.

In addition, a compound of the instant invention and second therapeuticagent may be administered by the same mode of administration, i.e. bothagents administered e.g. orally, by IV. However, it is also within thescope of the present invention to administer a compound of the instantinvention by one mode of administration, e.g. oral, and to administerthe second therapeutic agent by another mode of administration, e.g. IVor any other ones of the administration modes described hereinabove.

The first treatment procedure, administration of a compound of theinstant invention, can take place prior to the second treatmentprocedure, i.e., the second therapeutic agent, after the treatment withthe second therapeutic agent, at the same time as the treatment with thesecond therapeutic agent, or a combination thereof. For example, a totaltreatment period can be decided for a compound of the instant invention.The second therapeutic agent can be administered prior to onset oftreatment with a compound of the instant invention or followingtreatment with a compound of the instant invention. In addition,anti-cancer treatment can be administered during the period ofadministration of a compound of the instant invention but does not needto occur over the entire treatment period of a compound of the instantinvention.

The instant compounds are also useful in combination with therapeutic,chemotherapeutic and anti-cancer agents. Combinations of the presentlydisclosed compounds with therapeutic, chemotherapeutic and anti-canceragents are within the scope of the invention. Examples of such agentscan be found in Cancer Principles and Practice of Oncology by V. T.Devita and S. Hellman (editors), 6^(th) edition (Feb. 15, 2001),Lippincott Williams & Wilkins Publishers. A person of ordinary skill inthe art would be able to discern which combinations of agents would beuseful based on the particular characteristics of the drugs and thecancer involved. Such agents include the following: estrogen receptormodulators, androgen receptor modulators, retinoid receptor modulators,cytotoxic/cytostatic agents, antiproliferative agents, prenyl-proteintransferase inhibitors, HMG-CoA reductase inhibitors and otherangiogenesis inhibitors, HIV protease inhibitors, reverse transcriptaseinhibitors, inhibitors of cell proliferation and survival signaling,bisphosphonates, aromatase inhibitors, siRNA therapeutics, γ-secretaseinhibitors, agents that interfere with receptor tyrosine kinases (RTKs)and agents that interfere with cell cycle checkpoints. The instantcompounds are particularly useful when co-administered with radiationtherapy.

“Estrogen receptor modulators” refers to compounds that interfere withor inhibit the binding of estrogen to the receptor, regardless ofmechanism. Examples of estrogen receptor modulators include, but are notlimited to, tamoxifen, raloxifene, idoxifene, LY353381, LY117081,toremifene, fulvestrant,4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate,4,4′-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.

“Androgen receptor modulators” refers to compounds which interfere orinhibit the binding of androgens to the receptor, regardless ofmechanism. Examples of androgen receptor modulators include finasterideand other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide,liarozole, and abiraterone acetate.

“Retinoid receptor modulators” refers to compounds which interfere orinhibit the binding of retinoids to the receptor, regardless ofmechanism. Examples of such retinoid receptor modulators includebexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,α-difluoromethylornithine, ILX23-7553, trans-N-(4′-hydroxyphenyl)retinamide, and N-4-carboxyphenyl retinamide.

“Cytotoxic/cytostatic agents” refer to compounds which cause cell deathor inhibit cell proliferation primarily by interfering directly with thecell's functioning or inhibit or interfere with cell myosis, includingalkylating agents, tumor necrosis factors, intercalators, hypoxiaactivatable compounds, microtubule inhibitors/microtubule-stabilizingagents, inhibitors of mitotic kinesins, histone deacetylase inhibitors,inhibitors of kinases involved in mitotic progression, inhibitors ofkinases involved in growth factor and cytokine signal transductionpathways, antimetabolites, biological response modifiers,hormonal/anti-hormonal therapeutic agents, haematopoietic growthfactors, monoclonal antibody targeted therapeutic agents, topoisomeraseinhibitors, proteosome inhibitors, ubiquitin ligase inhibitors, andaurora kinase inhibitors.

Examples of cytotoxic/cytostatic agents include, but are not limited to,sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin,altretamine, prednimustine, dibromodulcitol, ranimustine, fotemustine,nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine,improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride,pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven,dexifosfamide, cis-aminedichloro(2-methyl-pyridine)platinum,benzylguanine, glufosfamide, GPX100, (trans, trans,trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro)platinum(II)]tetrachloride, diarizidinylspermine, arsenic trioxide,1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin,idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin,pinafide, valrubicin, amrubicin, antineoplaston,3′-deamino-3′-morpholino-13-deoxo-10-hydroxycarminomycin, annamycin,galarubicin, elinafide, MEN10755,4-demethoxy-3-deamino-3-aziridinyl-4-methylsulphonyl-daunorubicin (seeWO 00/50032), Raf kinase inhibitors (such as Bay43-9006) and mTORinhibitors (such as Wyeth's CCI-779).

An example of a hypoxia activatable compound is tirapazamine.

Examples of proteosome inhibitors include but are not limited tolactacystin and MLN-341 (Velcade).

Examples of microtubule inhibitors/microtubule-stabilising agentsinclude paclitaxel, vindesine sulfate,3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine, docetaxol, rhizoxin,dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881,BMS184476, vinflunine, cryptophycin,2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl) benzene sulfonamide,anhydrovinblastine,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide,TDX258, the epothilones (see for example U.S. Pat. Nos. 6,284,781 and6,288,237) and BMS188797. In an embodiment the epothilones are notincluded in the microtubule inhibitors/microtubule-stabilising agents.

Some examples of topoisomerase inhibitors are topotecan, hycaptamine,irinotecan, rubitecan,6-ethoxypropionyl-3′,4′-O-exo-benzylidene-chartreusin,9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H)propanamine,1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:b,7]-indolizino[1,2b]quinoline-10,13(9H,15H)dione,lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350,BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane,2′-dimethylamino-2′-deoxy-etoposide, GL331,N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide,asulacrine,(5a,5aB,8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydroxy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9-hexohydrofuro(3′,4′:6,7)naphtho(2,3-d)-1,3-dioxol-6-one,2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridinium,6,9-bis[(2-aminoethyl)amino]benzo[g]isoguinoline-5,10-dione,5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]acridin-6-one,N-[1-[2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide,N-(2-(dimethylamino)ethyl)acridine-4-carboxamide,6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one,and dimesna.

Examples of inhibitors of mitotic kinesins, and in particular the humanmitotic kinesin KSP, are described in Publications WO03/039460,WO03/050064, WO03/050122, WO03/049527, WO03/049679, WO03/049678,WO04/039774, WO03/079973, WO03/099211, WO03/105855, WO03/106417,WO04/037171, WO04/058148, WO04/058700, WO04/126699, WO05/018638,WO05/019206, WO05/019205, WO05/018547, WO05/017190, US2005/0176776. Inan embodiment inhibitors of mitotic kinesins include, but are notlimited to inhibitors of KSP, inhibitors of MKLP1, inhibitors of CENP-E,inhibitors of MCAK and inhibitors of Rab6-KIFL.

Examples of “histone deacetylase inhibitors” include, but are notlimited to, SAHA, TSA, oxamflatin, PXD101, MG98 and scriptaid. Furtherreference to other histone deacetylase inhibitors may be found in thefollowing manuscript; Miller, T. A. et al. J. Med. Chem.46(24):5097-5116 (2003).

“Inhibitors of kinases involved in mitotic progression” include, but arenot limited to, inhibitors of aurora kinase, inhibitors of Polo-likekinases (PLK; in particular inhibitors of PLK-1), inhibitors of bub-1and inhibitors of bub-R1. An example of an “aurora kinase inhibitor” isVX-680.

“Antiproliferative agents” includes antisense RNA and DNAoligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001,and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin,doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine,cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed,paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed,nelzarabine, 2′-deoxy-2′-methylidenecytidine,2′-fluoromethylene-2′-deoxycytidine,N-[5-(2,3-dihydro-benzofuryl)sulfonyl]-N′-(3,4-dichlorophenyl)urea,N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno-heptopyranosyl]adenine,aplidine, ecteinascidin, troxacitabine,4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][1,4]thiazin-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutamicacid, aminopterin, 5-flurouracil, alanosine,11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,11-diazatetracyclo(7.4.1.0.0)-tetradeca-2,4,6-trien-9-ylacetic acid ester, swainsonine, lometrexol, dexrazoxane, methioninase,2′-cyano-2′-deoxy-N4-palmitoyl-1-B-D-arabino furanosyl cytosine,3-aminopyridine-2-carboxaldehyde thiosemicarbazone and trastuzumab.

Examples of monoclonal antibody targeted therapeutic agents includethose therapeutic agents which have cytotoxic agents or radioisotopesattached to a cancer cell specific or target cell specific monoclonalantibody. Examples include Bexxar.

“HMG-CoA reductase inhibitors” refers to inhibitors of3-hydroxy-3-methylglutaryl-CoA reductase. Examples of HMG-CoA reductaseinhibitors that may be used include but are not limited to lovastatin(MEVACOR®; see U.S. Pat. Nos. 4,231,938, 4,294,926 and 4,319,039),simvastatin (ZOCOR®; see U.S. Pat. Nos. 4,444,784, 4,820,850 and4,916,239), pravastatin (PRAVACHOL®; see U.S. Pat. Nos. 4,346,227,4,537,859, 4,410,629, 5,030,447 and 5,180,589), fluvastatin (LESCOL®;see U.S. Pat. Nos. 5,354,772, 4,911,165, 4,929,437, 5,189,164,5,118,853, 5,290,946 and 5,356,896), atorvastatin (LIPITOR®; see U.S.Pat. Nos. 5,273,995, 4,681,893, 5,489,691 and 5,342,952) andcerivastatin (also known as rivastatin and BAYCHOL®; see U.S. Pat. No.5,177,080). The structural formulas of these and additional HMG-CoAreductase inhibitors that may be used in the instant methods aredescribed at page 87 of M. Yalpani, “Cholesterol Lowering Drugs”,Chemistry & Industry, pp. 85-89 (5 Feb. 1996) and U.S. Pat. Nos.4,782,084 and 4,885,314. The term HMG-CoA reductase inhibitor as usedherein includes all pharmaceutically acceptable lactone and open-acidforms (i.e., where the lactone ring is opened to form the free acid) aswell as salt and ester forms of compounds which have HMG-CoA reductaseinhibitory activity, and therefor the use of such salts, esters,open-acid and lactone forms is included within the scope of thisinvention.

“Prenyl-protein transferase inhibitor” refers to a compound whichinhibits any one or any combination of the prenyl-protein transferaseenzymes, including farnesyl-protein transferase (FPTase),geranylgeranyl-protein transferase type I (GGPTase-I), andgeranylgeranyl-protein transferase type-II (GGPTase-II, also called RabGGPTase).

Examples of prenyl-protein transferase inhibitors can be found in thefollowing publications and patents: WO 96/30343, WO 97/18813, WO97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO95/32987, U.S. Pat. Nos. 5,420,245, 5,523,430, 5,532,359, 5,510,510,5,589,485, 5,602,098, European Patent Publ. 0 618 221, European PatentPubl. 0 675 112, European Patent Publ. 0 604 181, European Patent Publ.0 696 593, WO 94/19357, WO 95/08542, WO 95/11917, WO 95/12612, WO95/12572, WO 95/10514, U.S. Pat. No. 5,661,152, WO 95/10515, WO95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO 96/05529, WO96/06138, WO 96/06193, WO 96/16443, WO 96/21701, WO 96/21456, WO96/22278, WO 96/24611, WO 96/24612, WO 96/05168, WO 96/05169, WO96/00736, U.S. Pat. No. 5,571,792, WO 96/17861, WO 96/33159, WO96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO 96/30362, WO96/30363, WO 96/31111, WO 96/31477, WO 96/31478, WO 96/31501, WO97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO97/17070, WO 97/23478, WO 97/26246, WO 97/30053, WO 97/44350, WO98/02436, and U.S. Pat. No. 5,532,359. For an example of the role of aprenyl-protein transferase inhibitor on angiogenesis see European J. ofCancer, Vol. 35, No. 9, pp. 1394-1401 (1999).

“Angiogenesis inhibitors” refers to compounds that inhibit the formationof new blood vessels, regardless of mechanism. Examples of angiogenesisinhibitors include, but are not limited to, tyrosine kinase inhibitors,such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFR1) andFlk-1/KDR (VEGFR2), inhibitors of epidermal-derived, fibroblast-derived,or platelet derived growth factors, MMP (matrix metalloprotease)inhibitors, integrin blockers, interferon-α, interleukin-12, pentosanpolysulfate, cyclooxygenase inhibitors, including nonsteroidalanti-inflammatories (NSAIDs) like aspirin and ibuprofen as well asselective cyclooxy-genase-2 inhibitors like celecoxib and rofecoxib(PNAS, Vol. 89, p. 7384 (1992); JNCI, Vol. 69, p. 475 (1982); Arch.Opthalmol., Vol. 108, p. 573 (1990); Anat. Rec., Vol. 238, p. 68 (1994);FEBS Letters, Vol. 372, p. 83 (1995); Clin, Orthop. Vol. 313, p. 76(1995); J. Mol. Endocrinol., Vol. 16, p. 107 (1996); Jpn. J. Pharmacol.,Vol. 75, p. 105 (1997); Cancer Res., Vol. 57, p. 1625 (1997); Cell, Vol.93, p. 705 (1998); Intl. J. Mol. Med., Vol. 2, p. 715 (1998); J. Biol.Chem., Vol. 274, p. 9116 (1999)), steroidal anti-inflammatories (such ascorticosteroids, mineralocorticoids, dexamethasone, prednisone,prednisolone, methylpred, betamethasone), carboxyamidotriazole,combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol,thalidomide, angiostatin, troponin-1, angiotensin II antagonists (seeFernandez et al., J. Lab. Clin. Med. 105:141-145 (1985)), and antibodiesto VEGF (see, Nature Biotechnology, Vol. 17, pp. 963-968 (October 1999);Kim et al., Nature, 362, 841-844 (1993); WO 00/44777; and WO 00/61186).

Other therapeutic agents that modulate or inhibit angiogenesis and mayalso be used in combination with the compounds of the instant inventioninclude agents that modulate or inhibit the coagulation and fibrinolysissystems (see review in Clin. Chem. La. Med. 38:679-692 (2000)). Examplesof such agents that modulate or inhibit the coagulation and fibrinolysispathways include, but are not limited to, heparin (see Thromb. Haemost.80:10-23 (1998)), low molecular weight heparins and carboxypeptidase Uinhibitors (also known as inhibitors of active thrombin activatablefibrinolysis inhibitor [TAFIa]) (see Thrombosis Res. 101:329-354(2001)). TAFIa inhibitors have been described in U.S. Ser. No.60/310,927 (filed Aug. 8, 2001) and 60/349,925 (filed Jan. 18, 2002).

“Agents that interfere with cell cycle checkpoints” refer to compoundsthat inhibit protein kinases that transduce cell cycle checkpointsignals, thereby sensitizing the cancer cell to DNA damaging agents.Such agents include inhibitors of ATR, ATM, the CHK1 and CHK2 kinasesand cdk and cdc kinase inhibitors and are specifically exemplified by7-hydroxystaurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032.

“Agents that interfere with receptor tyrosine kinases (RTKs)” refer tocompounds that inhibit RTKs and therefore mechanisms involved inoncogenesis and tumor progression. Such agents include inhibitors ofc-Kit, Eph, PDGF, Flt3 and c-Met. Further agents include inhibitors ofRTKs as described by Bume-Jensen and Hunter, Nature, 411:355-365, 2001.

“Inhibitors of cell proliferation and survival signalling pathway” referto compounds that inhibit signal transduction cascades downstream ofcell surface receptors. Such agents include inhibitors ofserine/threonine kinases (including but not limited to inhibitors of Aktsuch as described in WO 02/083064, WO 02/083139, WO 02/083140, US2004-0116432, WO 02/083138, US 2004-0102360, WO 03/086404, WO 03/086279,WO 03/086394, WO 03/084473, WO 03/086403, WO 2004/041162, WO2004/096131, WO 2004/096129, WO 2004/096135, WO 2004/096130, WO2005/100356, WO 2005/100344, US 2005/029941, US 2005/44294, US2005/43361, 60/734,188, 60/652,737, 60/670,469), inhibitors of Rafkinase (for example BAY-43-9006), inhibitors of MEK (for example CI-1040and PD-098059), inhibitors of mTOR (for example Wyeth CCI-779), andinhibitors of PI3K (for example LY294002).

As described above, the combinations with NSAID's are directed to theuse of NSAID's which are potent COX-2 inhibiting agents. For purposes ofthis specification an NSAID is potent if it possesses an IC₅₀ for theinhibition of COX-2 of 1 μM or less as measured by cell or microsomalassays.

The invention also encompasses combinations with NSAID's which areselective COX-2 inhibitors. For purposes of this specification NSAID'swhich are selective inhibitors of COX-2 are defined as those whichpossess a specificity for inhibiting COX-2 over COX-1 of at least 100fold as measured by the ratio of IC₅₀ for COX-2 over IC₅₀ for COX-1evaluated by cell or microsomal assays. Such compounds include, but arenot limited to those disclosed in U.S. Pat. Nos. 5,474,995, 5,861,419,6,001,843, 6,020,343, 5,409,944, 5,436,265, 5,536,752, 5,550,142,5,604,260, 5,698,584, 5,710,140, WO 94/15932, U.S. Pat. Nos. 5,344,991,5,134,142, 5,380,738, 5,393,790, 5,466,823, 5,633,272 and 5,932,598, allof which are hereby incorporated by reference.

Inhibitors of COX-2 that are particularly useful in the instant methodof treatment are: 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone;and5-chloro-3-(4-methylsulfonyl)-phenyl-2-(2-methyl-5-pyridinyl)pyridine;or a pharmaceutically acceptable salt thereof.

Compounds that have been described as specific inhibitors of COX-2 andare therefore useful in the present invention include, but are notlimited to, the following: parecoxib, BEXTRA® and CELEBREX® or apharmaceutically acceptable salt thereof.

Other examples of angiogenesis inhibitors include, but are not limitedto, endostatin, ukrain, ranpirnase, IM862,5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate,acetyldinanaline,5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-1H-1,2,3-triazole-4-carboxamide,CM101, squalamine, combretastatin, RPI4610, NX31838, sulfatedmannopentaose phosphate,7,7-(carbonyl-bis[imino-N-methyl-4,2-pyrrolocarbonylimino[N-methyl-4,2-pyrrole]-carbonylimino]-bis-(1,3-naphthalenedisulfonate), and 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone(SU5416).

As used above, “integrin blockers” refers to compounds which selectivelyantagonize, inhibit or counteract binding of a physiological ligand tothe α_(v)β₃ integrin, to compounds which selectively antagonize, inhibitor counteract binding of a physiological ligand to the αvβ5 integrin, tocompounds which antagonize, inhibit or counteract binding of aphysiological ligand to both the α_(v)β₃ integrin and the α_(v)β₅integrin, and to compounds which antagonize, inhibit or counteract theactivity of the particular integrin(s) expressed on capillaryendothelial cells. The term also refers to antagonists of the α_(v)β₆,α_(v)β₈, α₁β₁, α₂β₁, α₅β₁, α₆β₁ and α₆β₄ integrins. The term also refersto antagonists of any combination of α_(v)β₃, α_(v)β₅, α_(v)β₆, α_(v)β₈,α₁β₁, α₂β₁, α₅β₁, α₆β₁ and α₆β₄ integrins.

Some specific examples of tyrosine kinase inhibitors includeN-(trifluoromethylphenyl)-5-methylisoxazol-4-carboxamide,3-[(2,4-dimethylpyrrol-5-yl)methylidenyl)indolin-2-one,17-(allylamino)-17-demethoxygeldanamycin,4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxyl]quinazoline,N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine,BIBX1382,2,3,9,10,11,12-hexahydro-10-(hydroxymethyl)-10-hydroxy-9-methyl-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1-one,SH268, genistein, STI571, CEP2563,4-(3-chlorophenylamino)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidinemethanesulfonate, 4-(3-bromo-4-hydroxyphenyl)amino-6,7-dimethoxyquinazoline,4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, SU6668, STI571A,N-4-chlorophenyl-4-(4-pyridylmethyl)-1-phthalazinamine, and EMD121974.

Combinations with compounds other than anti-cancer compounds are alsoencompassed in the instant methods. For example, combinations of theinstantly claimed compounds with PPAR-γ (i.e., PPAR-gamma) agonists andPPAR-δ (i.e., PPAR-delta) agonists are useful in the treatment ofcertain malingnancies. PPAR-γ and PPAR-δ are the nuclear peroxisomeproliferator-activated receptors γ and δ. The expression of PPAR-γ onendothelial cells and its involvement in angiogenesis has been reportedin the literature (see J. Cardiovasc. Pharmacol. 1998; 31:909-913; J.Biol. Chem. 1999; 274:9116-9121; Invest. Ophthalmol Vis. Sci. 2000;41:2309-2317). More recently, PPAR-γ agonists have been shown to inhibitthe angiogenic response to VEGF in vitro; both troglitazone androsiglitazone maleate inhibit the development of retinalneovascularization in mice. (Arch. Ophthamol. 2001; 119:709-717).Examples of PPAR-γ agonists and PPAR-γ/α agonists include, but are notlimited to, thiazolidinediones (such as DRF2725, CS-011, troglitazone,rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate,GW2570, SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544,NN2344, KRP297, NP0110, DRF4158, NN622, GI262570, PNU182716, DRF552926,2-[(5,7-dipropyl-3-trifluoromethyl-1,2-benzisoxazol-6-yl)oxy]-2-methylpropionicacid (disclosed in U.S. Ser. No. 09/782,856), and2(R)-7-(3-(2-chloro-4-(4-fluorophenoxy)phenoxy)propoxy)-2-ethylchromane-2-carboxylic acid (disclosed in U.S.Ser. Nos. 60/235,708 and 60/244,697).

Another embodiment of the instant invention is the use of the presentlydisclosed compounds in combination with gene therapy for the treatmentof cancer. For an overview of genetic strategies to treating cancer seeHall et al (Am. J. Hum. Genet. 61:785-789, 1997) and Kufe et al (CancerMedicine, 5th Ed, pp 876-889, B C Decker, Hamilton 2000). Gene therapycan be used to deliver any tumor suppressing gene. Examples of suchgenes include, but are not limited to, p53, which can be delivered viarecombinant virus-mediated gene transfer (see U.S. Pat. No. 6,069,134,for example), a uPA/uPAR antagonist (“Adenovirus-Mediated Delivery of auPA/uPAR Antagonist Suppresses Angiogenesis-Dependent Tumor Growth andDissemination in Mice,” Gene Therapy, August 1998; 5(8):1105-13), andinterferon gamma (J. Immunol. 2000; 164:217-222).

The compounds of the instant invention may also be administered incombination with an inhibitor of inherent multidrug resistance (MDR), inparticular MDR associated with high levels of expression of transporterproteins. Such MDR inhibitors include inhibitors of p-glycoprotein(P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853 and PSC833(valspodar).

A compound of the present invention may be employed in conjunction withanti-emetic agents to treat nausea or emesis, including acute, delayed,late-phase, and anticipatory emesis, which may result from the use of acompound of the present invention, alone or with radiation therapy. Forthe prevention or treatment of emesis, a compound of the presentinvention may be used in conjunction with other anti-emetic agents,especially neurokinin-1 receptor antagonists, 5HT3 receptor antagonists,such as ondansetron, granisetron, tropisetron, and zatisetron, GABABreceptor agonists, such as baclofen, a corticosteroid such as Decadron(dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten orothers such as disclosed in U.S. Pat. Nos. 2,789,118, 2,990,401,3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712, anantidopaminergic, such as the phenothiazines (for exampleprochlorperazine, fluphenazine, thioridazine and mesoridazine),metoclopramide or dronabinol. In another embodiment, conjunctive therapywith an anti-emesis agent selected from a neurokinin-1 receptorantagonist, a 5HT3 receptor antagonist and a corticosteroid is disclosedfor the treatment or prevention of emesis that may result uponadministration of the instant compounds.

Neurokinin-1 receptor antagonists of use in conjunction with thecompounds of the present invention are fully described, for example, inU.S. Pat. Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595,5,459,270, 5,494,926, 5,496,833, 5,637,699, 5,719,147; European PatentPublication Nos. EP 0 360 390, 0 394 989, 0 428 434, 0 429 366, 0 430771, 0 436 334, 0 443 132, 0 482 539, 0 498 069, 0 499 313, 0 512 901, 0512 902, 0 514 273, 0 514 274, 0 514 275, 0 514 276, 0 515 681, 0 517589, 0 520 555, 0 522 808, 0 528 495, 0 532 456, 0 533 280, 0 536 817, 0545 478, 0 558 156, 0 577 394, 0 585 913, 0 590 152, 0 599 538, 0 610793, 0 634 402, 0 686 629, 0 693 489, 0 694 535, 0 699 655, 0 699 674, 0707 006, 0 708 101, 0 709 375, 0 709 376, 0 714 891, 0 723 959, 0 733632 and 0 776 893; PCT International Patent Publication Nos. WO90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151,92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 92/22569, 93/00330,93/00331, 93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 93/09116,93/10073, 93/14084, 93/14113, 93/18023, 93/19064, 93/21155, 93/21181,93/23380, 93/24465, 94/00440, 94/01402, 94/02461, 94/02595, 94/03429,94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/08997, 94/10165,94/10167, 94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767,94/15903, 94/19320, 94/19323, 94/20500, 94/26735, 94/26740, 94/29309,95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549,95/11880, 95/14017, 95/15311, 95/16679, 95/17382, 95/18124, 95/18129,95/19344, 95/20575, 95/21819, 95/22525, 95/23798, 95/26338, 95/28418,95/30674, 95/30687, 95/33744, 96/05181, 96/05193, 96/05203, 96/06094,96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661, 96/29304,96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553,97/01554, 97/03066, 97/08144, 97/14671, 97/17362, 97/18206, 97/19084,97/19942 and 97/21702; and in British Patent Publication Nos. 2 266 529,2 268 931, 2 269 170, 2 269 590, 2 271 774, 2 292 144, 2 293 168, 2 293169, and 2 302 689. The preparation of such compounds is fully describedin the aforementioned patents and publications, which are incorporatedherein by reference.

In an embodiment, the neurokinin-1 receptor antagonist for use inconjunction with the compounds of the present invention is selectedfrom:2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine,or a pharmaceutically acceptable salt thereof, which is described inU.S. Pat. No. 5,719,147.

A compound of the instant invention may also be administered with anagent useful in the treatment of anemia. Such an anemia treatment agentis, for example, a continuous erythropoiesis receptor activator (such asepoetin alfa).

A compound of the instant invention may also be administered with anagent useful in the treatment of neutropenia. Such a neutropeniatreatment agent is, for example, a hematopoietic growth factor whichregulates the production and function of neutrophils such as a humangranulocyte colony stimulating factor, (G-CSF). Examples of a G-CSFinclude filgrastim.

A compound of the instant invention may also be administered with animmunologic-enhancing drug, such as levamisole, isoprinosine andZadaxin.

A compound of the instant invention may also be useful for treating orpreventing cancer in combination with P450 inhibitors including:xenobiotics, quinidine, tyramine, ketoconazole, testosterone, quinine,methyrapone, caffeine, phenelzine, doxorubicin, troleandomycin,cyclobenzaprine, erythromycin, cocaine, furafyline, cimetidine,dextromethorphan, ritonavir, indinavir, amprenavir, diltiazem,terfenadine, verapamil, cortisol, itraconazole, mibefradil, nefazodoneand nelfinavir.

A compound of the instant invention may also be useful for treating orpreventing cancer in combination with Pgp and/or BCRP inhibitorsincluding: cyclosporin A, PSC833, GF120918, cremophorEL, fumitremorginC, Ko132, Ko134, Iressa, Imatnib mesylate, EKI-785, C11033, novobiocin,diethylstilbestrol, tamoxifen, resperpine, VX-710, tryprostatin A,flavonoids, ritonavir, saquinavir, nelfinavir, omeprazole, quinidine,verapamil, terfenadine, ketoconazole, nifidepine, FK506, amiodarone,XR9576, indinavir, amprenavir, cortisol, testosterone, LY335979,OC144-093, erythromycin, vincristine, digoxin and talinolol.

A compound of the instant invention may also be useful for treating orpreventing cancer, including bone cancer, in combination withbisphosphonates (understood to include bisphosphonates, diphosphonates,bisphosphonic acids and diphosphonic acids). Examples of bisphosphonatesinclude but are not limited to: etidronate (Didronel), pamidronate(Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate(Zometa), ibandronate (Boniva), incadronate or cimadronate, clodronate,EB-1053, minodronate, neridronate, piridronate and tiludronate includingany and all pharmaceutically acceptable salts, derivatives, hydrates andmixtures thereof.

A compound of the instant invention may also be useful for treating orpreventing breast cancer in combination with aromatase inhibitors.Examples of aromatase inhibitors include but are not limited to:anastrozole, letrozole and exemestane.

A compound of the instant invention may also be useful for treating orpreventing cancer in combination with siRNA therapeutics.

The compounds of the instant invention may also be administered incombination with γ-secretase inhibitors and/or inhibitors of NOTCHsignaling. Such inhibitors include compounds described in WO 01/90084,WO 02/30912, WO 01/70677, WO 03/013506, WO 02/36555, WO 03/093252, WO03/093264, WO 03/093251, WO 03/093253, WO 2004/039800, WO 2004/039370,WO 2005/030731, WO 2005/014553, U.S. Ser. No. 10/957,251, WO2004/089911, WO 02/081435, WO 02/081433, WO 03/018543, WO 2004/031137,WO 2004/031139, WO 2004/031138, WO 2004/101538, WO 2004/101539 and WO02/47671 (including LY-450139).

A compound of the instant invention may also be useful for treating orpreventing cancer in combination with PARP inhibitors.

A compound of the instant invention may also be useful for treatingcancer in combination with the following therapeutic agents: abarelix(Plenaxis Depot®); aldesleukin (Prokine®); Aldesleukin (Proleukin®);Alemtuzumabb (Campath®); alitretinoin (Panretin®); allopurinol(Zyloprim®); altretamine (Hexalen®); amifostine (Ethyol®); anastrozole(Arimidex®); arsenic trioxide (Trisenox®); asparaginase (Elspar®);azacitidine (Vidaza®); bevacuzimab (Avastin®); bexarotene capsules(Targretin®); bexarotene gel (Targretin®); bleomycin (Blenoxane®);bortezomib (Velcade®); busulfan intravenous (Busulfex®); busulfan oral(Myleran®); calusterone (Methosarb®); capecitabine (Xeloda®);carboplatin (Paraplatin®); carmustine (BCNU®, BiCNU®); carmustine(Gliadel®); carmustine with Polifeprosan 20 Implant (Gliadel Wafer®);celecoxib (Celebrex®); cetuximab (Erbitux®); chlorambucil (Leukeran®);cisplatin (Platinol®); cladribine (Leustatin®, 2-CdA®); clofarabine(Clolar®); cyclophosphamide (Cytoxan®, Neosar®); cyclophosphamide(Cytoxan Injection®); cyclophosphamide (Cytoxan Tablet®); cytarabine(Cytosar-U®); cytarabine liposomal (DepoCyt®); dacarbazine (DTIC-Dome®);dactinomycin, actinomycin D (Cosmegen®); Darbepoetin alfa (Aranesp®);daunorubicin liposomal (DanuoXome®); daunorubicin, daunomycin(Daunorubicin®); daunorubicin, daunomycin (Cerubidine®); Denileukindiftitox (Ontak®); dexrazoxane (Zinecard®); docetaxel (Taxotere®);doxorubicin (Adriamycin PFS®); doxorubicin (Adriamycin®, Rubex®);doxorubicin (Adriamycin PFS Injection®); doxorubicin liposomal (Doxil®);DROMOSTANOLONE PROPIONATE (DROMOSTANOLONE®); DROMOSTANOLONE PROPIONATE(MASTERONE INJECTION®); Elliott's B Solution (Elliott's B Solution®);epirubicin (Ellence®); Epoetin alfa (Epogen®); erlotinib (Tarceva®);estramustine (Emcyt®); etoposide phosphate (Etopophos®); etoposide,VP-16 (Vepesid®); exemestane (Aromasin®); Filgrastim (Neupogen®);floxuridine (intraarterial) (FUDR®); fludarabine (Fludara®);fluorouracil, 5-FU (Adrucil®); fulvestrant (Faslodex®); gefitinib(Iressa®); gemcitabine (Gemzar®); gemtuzumab ozogamicin (Mylotarg®);goserelin acetate (Zoladex Implant®); goserelin acetate (Zoladex®);histrelin acetate (Histrelin Implant®); hydroxyurea (Hydrea®);Ibritumomab Tiuxetan (Zevalin®); idarubicin (Idamycin®); ifosfamide(IFEX®); imatinib mesylate (Gleevec®); interferon alfa 2a (Roferon A®);Interferon alfa-2b (Intron A®); irinotecan (Camptosar®); lenalidomide(Revlimid®); letrozole (Femara®); leucovorin (Wellcovorin®,Leucovorin®); Leuprolide Acetate (Eligard®); levamisole (Ergamisol®);lomustine, CCNU (CeeBU®); meclorethamine, nitrogen mustard (Mustargen®);megestrol acetate (Megace®); melphalan, L-PAM (Alkeran®);mercaptopurine, 6-MP (Purinethol®); mesna (Mesnex®); mesna (MesnexTabs®); methotrexate (Methotrexate®); methoxsalen (Uvadex®); mitomycin C(Mutamycin®); mitotane (Lysodren®); mitoxantrone (Novantrone®);nandrolone phenpropionate (Durabolin-50®); nelarabine (Arranon®);Nofetumomab (Verluma®); Oprelvekin (Neumega®); oxaliplatin (Eloxatin®);paclitaxel (Paxene®); paclitaxel (Taxol®); paclitaxel protein-boundparticles (Abraxane®); palifermin (Kepivance®); pamidronate (Aredia®);pegademase (Adagen (Pegademase Bovine)®); pegaspargase (Oncaspar®);Pegfilgrastim (Neulasta®); pemetrexed disodium (Alimta®); pentostatin(Nipent®); pipobroman (Vercyte®); plicamycin, mithramycin (Mithracin®);porfimer sodium (Photofrin®); procarbazine (Matulane®); quinacrine(Atabrine®); Rasburicase (Elitek®); Rituximab (Rituxan®); Ridaforolimus;sargramostim (Leukine®); Sargramostim (Prokine®); sorafenib (Nexavar®);streptozocin (Zanosar®); sunitinib maleate (Sutent®); talc (Sclerosol®);tamoxifen (Nolvadex®); temozolomide (Temodar®); teniposide, VM-26(Vumon®); testolactone (Teslac®); thioguanine, 6-TG (Thioguanine®);thiotepa (Thioplex®); topotecan (Hycamtin®); toremifene (Fareston®);Tositumomab (Bexxar®); Tositumomab/I-131 tositumomab (Bexxar®);Trastuzumab (Herceptin®); tretinoin, ATRA (Vesanoid®); Uracil Mustard(Uracil Mustard Capsules®); valrubicin (Valstar®); vinblastine(Velban®); vincristine (Oncovin®); vinorelbine (Navelbine®); vorinostat(Zolinza®) and zoledronate (Zometa®).

In an embodiment, the angiogenesis inhibitor to be used as the secondcompound is selected from a tyrosine kinase inhibitor, an inhibitor ofepidermal-derived growth factor, an inhibitor of fibroblast-derivedgrowth factor, an inhibitor of platelet derived growth factor, an MMP(matrix metalloprotease) inhibitor, an integrin blocker, interferon-α,interleukin-12, pentosan polysulfate, a cyclooxygenase inhibitor,carboxyamidotriazole, combretastatin A-4, squalamine,6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin,troponin-1, or an antibody to VEGF. In an embodiment, the estrogenreceptor modulator is tamoxifen or raloxifene.

Thus, the scope of the instant invention encompasses the use of theinstantly claimed compounds in combination with a second compoundselected from: an estrogen receptor modulator, an androgen receptormodulator, a retinoid receptor modulator, a cytotoxic/cytostatic agent,an antiproliferative agent, a prenyl-protein transferase inhibitor, anHMG-CoA reductase inhibitor, an HIV protease inhibitor, a reversetranscriptase inhibitor, an angiogenesis inhibitor, PPAR-γ agonists,PPAR-δ agonists, an inhibitor of inherent multidrug resistance, ananti-emetic agent, an agent useful in the treatment of anemia, an agentuseful in the treatment of neutropenia, an immunologic-enhancing drug,an inhibitor of cell proliferation and survival signaling, abisphosphonate, an aromatase inhibitor, an siRNA therapeutic,γ-secretase and/or NOTCH inhibitors, agents that interfere with receptortyrosine kinases (RTKs), an agent that interferes with a cell cyclecheckpoint, and any of the therapeutic agents listed above.

Also included in the scope of the claims is a method of treating cancerthat comprises administering a therapeutically effective amount of acompound of the instant invention in combination with radiation therapyand/or in combination with a second compound selected from: an estrogenreceptor modulator, an androgen receptor modulator, a retinoid receptormodulator, a cytotoxiccytostatic agent, an antiproliferative agent, aprenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, anHIV protease inhibitor, a reverse transcriptase inhibitor, anangiogenesis inhibitor, PPAR-γ agonists, PPAR-δ agonists, an inhibitorof inherent multidrug resistance, an anti-emetic agent, an agent usefulin the treatment of anemia, an agent useful in the treatment ofneutropenia, an immunologic-enhancing drug, an inhibitor of cellproliferation and survival signaling, a bisphosphonate, an aromataseinhibitor, an siRNA therapeutic, γ-secretase and/or NOTCH inhibitors,agents that interfere with receptor tyrosine kinases (RTKs), an agentthat interferes with a cell cycle checkpoint, and any of the therapeuticagents listed above.

And yet another embodiment of the invention is a method of treatingcancer that comprises administering a therapeutically effective amountof a compound of the instant invention in combination with paclitaxel ortrastuzumab.

The invention further encompasses a method of treating or preventingcancer that comprises administering a therapeutically effective amountof a compound of the instant invention in combination with a COX-2inhibitor.

The instant invention also includes a pharmaceutical composition usefulfor treating or preventing cancer that comprises a therapeuticallyeffective amount of a compound of the instant invention and a secondcompound selected from: an estrogen receptor modulator, an androgenreceptor modulator, a retinoid receptor modulator, acytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-proteintransferase inhibitor, an HMG-CoA reductase inhibitor, an HIV proteaseinhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor,a PPAR-γ agonist, a PPAR-δ agonist, an inhibitor of cell proliferationand survival signaling, a bisphosphonate, an aromatase inhibitor, ansiRNA therapeutic, γ-secretase and/or NOTCHinhibitors, agents thatinterfere with receptor tyrosine kinases (RTKs), an agent thatinterferes with a cell cycle checkpoint, and any of the therapeuticagents listed above.

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR), e.g., 1996edition (Medical Economics Company, Montvale, N.J. 07645-1742, USA), thePhysicians'Desk Reference, 56^(th) Edition, 2002 (published by MedicalEconomics company, Inc. Montvale, N.J. 07645-1742), the Physicians' DeskReference, 57^(th) Edition, 2003 (published by Thompson PDR, Montvale,N.J. 07645-1742), the Physicians' Desk Reference, 60^(th) Edition, 2006(published by Thompson PDR, Montvale, N.J. 07645-1742), and thePhysicians' Desk Reference, 64^(th) Edition, 2010 (published by PDRNetwork, LLC at Montvale, N.J. 07645-1725); the disclosures of which areincorporated herein by reference thereto.

If the patient is responding, or is stable, after completion of thetherapy cycle, the therapy cycle can be repeated according to thejudgment of the skilled clinician. Upon completion of the therapycycles, the patient can be continued on the compounds of this inventionat the same dose that was administered in the treatment protocol. Thismaintenance dose can be continued until the patient progresses or can nolonger tolerate the dose (in which case the dose can be reduced and thepatient can be continued on the reduced dose).

Those skilled in the art will recognize that the actual dosages andprotocols for administration employed in the methods of this inventionmay be varied according to the judgment of the skilled clinician. Theactual dosage employed may be varied depending upon the requirements ofthe patient and the severity of the condition being treated.Determination of the proper dosage for a particular situation is withinthe skill of the art. A determination to vary the dosages and protocolsfor administration may be made after the skilled clinician takes intoaccount such factors as the patient's age, condition and size, as wellas the severity of the cancer being treated and the response of thepatient to the treatment.

The amount and frequency of administration of the compound of formula(1) and the chemotherapeutic agents will be regulated according to thejudgment of the attending clinician (physician) considering such factorsas age, condition and size of the patient as well as severity of thecancer being treated.

The chemotherapeutic agent can be administered according to therapeuticprotocols well known in the art. It will be apparent to those skilled inthe art that the administration of the chemotherapeutic agent can bevaried depending on the cancer being treated and the known effects ofthe chemotherapeutic agent on that disease. Also, in accordance with theknowledge of the skilled clinician, the therapeutic protocols (e.g.,dosage amounts and times of administration) can be varied in view of theobserved effects of the administered therapeutic agents on the patient,and in view of the observed responses of the cancer to the administeredtherapeutic agents.

The initial administration can be made according to establishedprotocols known in the art, and then, based upon the observed effects,the dosage, modes of administration and times of administration can bemodified by the skilled clinician.

The particular choice of chemotherapeutic agent will depend upon thediagnosis of the attending physicians and their judgement of thecondition of the patient and the appropriate treatment protocol.

The determination of the order of administration, and the number ofrepetitions of administration of the chemotherapeutic agent during atreatment protocol, is well within the knowledge of the skilledphysician after evaluation of the cancer being treated and the conditionof the patient.

Thus, in accordance with experience and knowledge, the practicingphysician can modify each protocol for the administration of achemotherapeutic agent according to the individual patient's needs, asthe treatment proceeds. All such modifications are within the scope ofthe present invention.

The attending clinician, in judging whether treatment is effective atthe dosage administered, will consider the general well-being of thepatient as well as more definite signs such as relief of cancer-relatedsymptoms (e.g., pain), inhibition of tumor growth, actual shrinkage ofthe tumor, or inhibition of metastasis. Size of the tumor can bemeasured by standard methods such as radiological studies, e.g., CAT orMRI scan, and successive measurements can be used to judge whether ornot growth of the tumor has been retarded or even reversed. Relief ofdisease-related symptoms such as pain, and improvement in overallcondition can also be used to help judge effectiveness of treatment.

The compounds of this invention may be prepared by employing reactionsas shown in the following Reaction Schemes, in addition to otherstandard manipulations that are known in the literature or exemplifiedin the experimental procedures. The illustrative Reaction Schemes below,therefore, are not limited by the compounds listed or by any particularsubstituents employed for illustrative purposes. Substituent numberingas shown in the Reaction Schemes do not necessarily correlate to thatused in the claims and often, for clarity, a single substituent is shownattached to the compound where multiple substituents are optionallyallowed under the definitions of formula (I) hereinabove.

SCHEMES

In Scheme 1 5-bromo-6-nitro-1H-indazole (S1) is subjected to a metalcatalyzed or metal-facilitated process (such as Stille or Suzukicoupling) to provide olefin S2, which is then converted to S3 (X¹═Cl,Br, or I) by techniques well known in the art (such as treatment withNaOCl, N-chlorosuccinimide, N-bromosuccinimide, Br₂, N-iodosuccinimideor I₂, with or without a base such as KOH, NaOH, K₂CO₃, Cs₂CO₃, orLiHMDS; or I₂/Ag₂SO₄). Compound S3 can then be protected with aprotecting group (PG) such as trityl, BOC, or SEM. The resultingcompound S4 is converted to the aldehyde S5 by ozonolysis, treatmentwith OsO₄/NaIO₄, or another technique well known in the art and is thensubjected to a reductive amination with an appropriate primary amine.The nitro group in S6 is then reduced (e.g. using Zn, Fe, Pd(OH)₂—H₂,Pt/V—H₂, SnCl₂ or other reagent well known in the art) and the resultingamine is cyclized with triphosgene, CDI, 4-nitrophenyl chloroformate, orother appropriate reagent to provide S7. Compound S8 is then obtainedusing a metal catalyzed or metal-facilitated C—C, C—N, or C—O process(such as Stille, Suzuki, Negishi, Buchwald or other coupling) or otherappropriate chemical transformation. Compound S9 is obtained through aprotecting group (PG) deprotection step (e.g. TFA for PG=Boc, trityl orSEM).

In Scheme 2 compound S1 is first halogenated (as described in Scheme 1),protected, and then is subjected to further derivatization at theC3-position (via a metal catalyzed or metal-facilitated process, such asStille, Suzuki, Negishi, or Buchwald coupling. The resulting compoundS11 is then converted to the aldehyde S12 (as described in Scheme 1 orby another method such as lithium halogen exchange followed electrophilequench, e.g. nBuLi/DMF) and is subjected to the reductiveamination-nitro reduction-ring closure sequence described in Scheme 1.

In Scheme 3 compound S11 is converted to S14 (via a metal catalyzed ormetal-facilitated process, such as Stille coupling, Suzuki coupling, orNegishi coupling. The nitro group in S14 is then reduced and cyclized toprovide S15, which is deprotected to provide S16.

In Scheme 4 compound S15a is optionally protected with an additionalprotecting group (such as BOC) and then is further substituted once ortwice by treatment with an appropriate base and electrophile. Theresulting compound S16a is then deprotected.

In Scheme 5 the methyl ester S18a or S18b is subjected to a sequencesimilar to that described in Scheme 2 (sequential C3-halogenation,C3-coupling and N1-protection) to provide S21a or S21b. Subsequentcoupling of S21b (Y¹═Cl) with an appropriate urea (such as benzyl urea)and concomitant ring closing provides S22. Alternatively, S22 isaccessed from S21a (Y¹═NO₂) via sequential nitro reduction, reactionwith an appropriate isocyanate (such as benzyl isocyanate) and ringclosure.

In Scheme 6 S7 (X¹═Cl, Br, or I) undergoes a C—O or C—N coupling at theC3 position. The C—O coupling of S7 (X¹═Br or I) with an appropriatealcohol to provide S24a can be achieved using CuI (with an appropriatebase such as Cs₂CO₃ and an appropriate ligand such astetramethylphenanthroline, e.g. see Buchwald et. al. J. Org. Chem.,2008, 73, 284) or via a palladium-catalyzed process (with an appropriatephosphine ligand such as RockPhos; e.g. see Buchwald et. al. Angew.Chem. Int. Ed. 2011, 50, 9943 or JosiPhos, e.g. see Maligres et. al.Angew. Chem. Int. Ed. 2012, 51, 9071 or tBuXPhos, see Buchwald et. al.Angew. Chem. Int. Ed., 2006, 45, 4321). The C—N coupling of S7 (X¹═Cl,Br, or I) with an appropriate amine to provide S24b may be achievedusing a palladium precatalyst such as BrettPhos precatalyst, tBuXPhosprecatalyst, Xphos precatalyst, RuPhos precatalyst or Sphos precatalystand an appropriate base such as NaOtBu, Cs₂CO₃ or K₃PO₄ (see e.g.Buchwald et. al., Chem. Sci., 2011, 2, 27). Alternatively, the C—Ncoupling of S7 (X¹═I) with an appropriate amine to provide S24b may beachieved using CuI or Bu₄NCuI₂ with an appropriate base (such as Cs₂CO₃or K₃PO₄) and appropriate ligand such as tetramethylphenanthroline,2-isobutyrylcyclohexanone, ortrans-N,N′-dimethylcyclohexane-1,2-diamine. Compound 24a or 24b is thendeprotected.

In Scheme 7 compound S7 is coupled with 2,4-dimethoxybenzylamine (DMB,using BrettPhos Pd-precatalyst or the like) to provide S26 which isfurther acylated to provide S27 (e.g. in which R¹² can be Ac using AcCl;R¹² may be CO₂Me using ClCO₂Me; or a similar acylation). Alternatively,S26 can undergo a reductive amination with an appropriately substitutedaldehyde or a S_(N)2 or S_(N)Ar-type reaction with an appropriateelectrophile. Final global deprotection with a reagent such as TFA canbe used to remove the DMB and N1-protecting group (e.g. when it is Boc,Tr, or SEM). In another embodiment, S26 can be converted directly to S28by global deprotection (R¹²═H).

In Scheme 8 5,6-dibromo-1H-pyrazolo[4,3-b]pyridine (S29) (which iscommerically available or alternatively may be synthesized from5-bromo-2-methyl-3-nitropyridine (see PCT Int. Appl., 2010056999, 20 May2010)) is subjected to a metal catalyzed or metal-facilitated process(such as Stille or Suzuki coupling) to provide olefin S30, which is thenprotected with an appropriate protecting group (e.g. SEM). The resultingcompound S31 (Y═Br) is subjected to an amination with an appropriatelyprotected amine (e.g. BOC—NH₂, CBz-NH₂, BnNH₂ etc) to provide S32(Y¹═NH—PG). In a manner similar to that described in Scheme 1, S32 isconverted to the aldehyde S33 (e.g. by ozonolysis or treatment withOsO₄/NaIO₄) and then to S34 by reductive amination with an appropriateprimary amine. Selective deprotection of S34 is followed by cyclizationwith triphosgene, CDI, 4-nitrophenyl chloroformate, or other appropriatereagent. The resulting compound S35 is iodinated (e.g. with AgSO₄/I₂),coupled with an appropriate R¹ group and deprotected to provide S37.Alternatively, the deprotection step is performed first, followed byhalogenation (e.g. X¹═Cl, Br, or I by a method such as treatment withNaOCl, N-chlorosuccinimide, N-bromosuccinimide, Br₂, N-iodosuccinimideor I₂, with or without a base such as KOH, NaOH, K₂CO₃, Cs₂CO₃, orLiHMDS) and final coupling.

In Scheme 9 S1 is iodinated and protected in a manner similar to thatpreviously described in Scheme 1 (PG=SEM, Boc, Tr or other appropriategroup). The resulting compound S38 is subjected to a metal catalyzed ormetal-facilitated C—C, C—N, or C—O process (such as Stille, Suzuki,Negishi, or Buchwald coupling) to provide S39. Compound S39 is thenconverted to S40 by one of a number of techniques known in the art (suchas a metal catalyzed carbonylation reaction, lithium-halogen exchange orGrignard formation followed by quench with an appropriate electrophile,or metal catalyzed C—C coupling with an appropriate partner such asn-butyl vinyl ether or (1-ethoxyethenyl)tributyltin, followed by acidtreatment). Compound S40 is then converted sequentially to S41 and thenS42 in a manner similar to that previously described in Scheme 1.

Alternatively, in Scheme 10 compound S5 (X¹═Cl, Br, or I) is treatedwith an appropriate nucleophile (such as a Grignard or lithiatedspecies) and the resulting alcohol is then oxidized to provide theketone S43, which is further elaborated as previously described (i.e.Schemes 1 and 9).

EXAMPLES Example 13-(2-methylpyridin-4-yl)-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one

Step 1

To a stirred solution of 5-bromo-6-nitro-1H-indazole (10.0 g, 41.3 mmol)in DMF (41 mL) were added iodine (21.0 g, 83 mmol) and potassiumhydroxide (8.69 g, 155 mmol). The mixture was left to stir overnight,treated with aqueous sodium thiosulfate solution, and filtered through afritted glass. The solid was washed with water and dried under vacuum toafford 5-bromo-3-iodo-6-nitro-1H-indazole as an orange solid. ¹H NMR(600 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.92 (s, 1H).

Step 2

To a stirred solution of 5-bromo-3-iodo-6-nitro-1H-indazole (9.21 g,25.0 mmol) in THF (78 mL) was added NaH (60%, 1.3 g, 32.5 mmol) at 0° C.The mixture was left to stir at 0° C. for 30 min and treated withtrityl-Cl (7.68 g, 27.5 mmol). The bath was removed and the mixture wasleft to stir overnight. The mixture was cooled to 0° C. and treated withaqueous ammonium chloride solution. The mixture was concentrated to halfa volume, and filtered through a fritted glass. The brown solid waswashed with hexanes, and dried under high vacuum to afford5-bromo-3-iodo-6-nitro-1-trityl-1H-indazole. ¹H NMR (600 MHz, DMSO-d6) δ7.98 (s, 1H), 7.16-7.38 (m, 15H), 6.74 (s, 1H).

Step 3

A mixture of 5-bromo-3-iodo-6-nitro-1-trityl-1H-indazole (13.0 g, 21.3mmol), 2-methylpyridine-4-boronic acid (3.79 g, 27.7 mmol),PdCl₂(dppf)-CH₂Cl₂ (1.74 g, 2.13 mmol), and cesium carbonate (20.8 g,63.9 mmol) in THF (107 mL) was purged with nitrogen for 10 min, andheated to 80° C. overnight. The mixture was cooled to room temperature,and treated with water. THF was evaporated, and the residue wasextracted with EtOAc (×3). The combined organics were washed with brine,dried (sodium sulfate), concentrated, and purified by flashchromatography to afford5-bromo-3-(2-methylpyridin-4-yl)-6-nitro-1-trityl-1H-indazole. MS:[M+H]⁺ m/z 575. ¹H NMR (600 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.55 (d, J=5.3Hz, 1H), 7.78 (s, 1H), 7.67 (d, J=5.0 Hz, 1H), 7.22-7.41 (m, 15H), 6.82(s, 1H), 2.57 (s, 3H).

Step 4

A mixture of5-bromo-3-(2-methylpyridin-4-yl)-6-nitro-1-trityl-1H-indazole (3.5 g,6.1 mmol), methyl acrylate (5.24 g, 60.8 mmol), Pd(OAc)₂ (0.14 g, 0.61mmol), tri-o-tolylphosphine (0.37 g, 1.22 mmol), and triethylamine (1.85g, 18.3 mmol) in toluene (30 mL) was purged with nitrogen for 5 min, andheated to 70° C. overnight. Additional methyl acrylate (4.8 g, 56 mmol)was added to the mixture and the resultant solution was heated to 70° C.overnight. The mixture was treated with water, and extracted with EtOAc(×3). The combined organics were washed with brine, dried (sodiumsulfate), and concentrated. The residue was triturated with ether andhexanes to afford methyl(2E)-3-[3-(2-methylpyridin-4-yl)-6-nitro-1-trityl-1H-indazol-5-yl]prop-2-enoate.MS: [M+H]⁺ m/z 581. ¹H NMR (600 MHz, DMSO-d6) δ 8.58 (d, J=5.0 Hz, 1H),8.56 (s, 1H), 7.89 (d, J=15.8 Hz, 1H), 7.80 (s, 1H), 7.77 (d, J=5.0 Hz,1H), 7.22-7.42 (m, 15H), 6.97 (s, 1H), 6.81 (d, J=15.9 Hz, 1H), 3.75 (s,3H), 2.57 (s, 3H).

Steps 5-6

To a stirred solution of(2E)-3-[3-(2-methylpyridin-4-yl)-6-nitro-1-trityl-1H-indazol-5-yl]prop-2-enoate(3.5 g, 6.0 mmol) in ethanol (30 mL) was added Zn (1.97 g, 30.1 mmol)and saturated ammonium chloride solution (10 mL). The mixture was heatedto 80° C. for 5 h. Additional Zn (2.0 g, 30 mmol) was added and themixture was heated to 80° C. overnight. The mixture was treated with Zn(2.0 g, 30 mmol) and heated to 80° C. for 1 day. The mixture was cooledto room temperature, filtered through a pad of Celite, and washed with10% MeOH in DCM. The filtrate was concentrated, diluted with water, andextracted with EtOAc (×3). The combined organics were dried (sodiumsulfate) and concentrated to provide methyl3-(6-amino-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazol-5-yl)acrylate,which was used in the next step without further purification. MS: [M+H]⁺m/z 551.

To a stirred solution of the crude product in xylene (126 mL) was addedpiperidine (3.22 g, 37.8 mmol). The reaction mixture was heated to 130°C. for 3 days, cooled to room temperature, and concentrated. The residuewas purified by flash chromatography to afford3-(2-methylpyridin-4-yl)-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-oneand3-(2-methylpyridin-4-yl)-1-trityl-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one.For3-(2-methylpyridin-4-yl)-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one;MS: [M+H]⁺ m/z 277. ¹H NMR (600 MHz, DMSO-d6) δ 13.54 (s, 1H), 11.67 (s,1H), 8.62 (s, 1H), 8.60 (d, J=4.7 Hz, 1H), 8.07 (d, J=9.7 Hz, 1H), 7.96(s, 1H), 7.89 (d, J=4.4 Hz, 1H), 7.41 (s, 1H), 6.44 (d, J=9.4 Hz, 1H),2.60 (s, 3H). For3-(2-methylpyridin-4-yl)-1-trityl-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one;MS: [M+H]⁺ m/z 519. ¹H NMR (600 MHz, DMSO-d6) δ 11.36 (s, 1H), 8.57 (s,1H), 8.55 (d, J=5.3 Hz, 1H), 8.00 (d, J=9.7 Hz, 1H), 7.77 (s, 1H), 7.67(d, J=4.1 Hz, 1H), 7.24-7.36 (m, 15H), 6.62 (s, 1H), 6.39 (d, J=9.7 Hz,1H), 2.56 (s, 3H).

Example 26-bromo-3-(2-methylpyridin-4-yl)-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one

Step 1

To a stirred solution of3-(2-methylpyridin-4-yl)-1-trityl-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one(1.8 g, 3.5 mmol) in DCM (69 mL) was added NBS (0.62 g, 3.5 mmol). Themixture was left to stir for 4 h, treated with additional NBS (0.62 g,3.5 mmol), and left to stir overnight. The mixture was treated withadditional NBS (0.5 g, 2.8 mmol) and left to stir for 5 h. The mixturewas treated with aqueous Na₂S₂O₃ solution, and extracted with EtOAc(×3). The combined organics were dried (sodium sulfate), concentrated,and purified by flash chromatography. The fractions were combined,concentrated, washed with water, and dried under high vacuum to afford6-bromo-3-(2-methylpyridin-4-yl)-1-trityl-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one.MS: [M+H]⁺ m/z 597.

To a stirred solution of6-bromo-3-(2-methylpyridin-4-yl)-1-trityl-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one(40 mg, 0.067 mmol) in DCM (2 mL) were added TFA (0.4 mL) andtriethylsilane (30 μL, 0.19 mmol). The reaction mixture was left to stirfor 3 h, concentrated, and purified by prep-HPLC. The desired fractionswere treated with saturated NaHCO₃ solution, and extracted with DCM(×3). The combined organics were dried (sodium sulfate), concentrated,and dried under high vacuum to afford6-bromo-3-(2-methylpyridin-4-yl)-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one.MS: [M+H]⁺ m/z 355. ¹H NMR (600 MHz, DMSO-d6) δ 13.55 (s, 1H), 12.15 (s,1H), 8.65 (s, 1H), 8.64 (s, 1H), 8.58 (d, J=5.0 Hz, 1H), 7.89 (s, 1H),7.82 (d, J=5.0 Hz, 1H), 7.43 (s, 1H), 2.60 (s, 3H).

Example 36-benzyl-3-(2-methylpyridin-4-yl)-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one

Steps 1-2

A mixture of6-bromo-3-(2-methylpyridin-4-yl)-1-trityl-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one(52 mg, 0.087 mmol), potassium benzyltrifluoroborate (43 mg, 0.22 mmol),PdCl₂(dppf)-CH₂Cl₂ (7.1 mg, 0.0087 mmol), and cesium carbonate (85 mg,0.26 mmol) in THF (1.6 mL)/water (0.16 mL) was purged with nitrogen for5 min, heated to 70° C. overnight, and cooled to room temperature. Themixture was treated with water, and extracted with EtOAc (×3). Thecombined organics were washed with brine, dried (sodium sulfate),concentrated, and purified by flash chromatography to afford6-benzyl-3-(2-methylpyridin-4-yl)-1-trityl-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one.MS: [M+H]⁺ m/z 609.

Step 2

TFA (0.2 mL, 2.60 mmol) and triethylsilane (0.012 mL, 0.072 mmol) wereadded to a stirred solution of6-benzyl-3-(2-methylpyridin-4-yl)-1-trityl-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one(44 mg, 0.072 mmol) in DCM (2 mL) and the mixture was stirred at roomtemperature for 3 h. The mixture was concentrated, diluted with DCM, andtreated with saturated sodium bicarbonate solution. The organic layerwas separated, concentrated, and purified by flash chromatography toafford6-benzyl-3-(2-methylpyridin-4-yl)-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one.MS: [M+H]⁺ m/z 367. ¹H NMR (600 MHz, DMSO-d6) δ 13.42 (s, 1H), 11.74 (s,1H), 8.54 (d, J=5.3 Hz, 1H), 8.52 (s, 1H), 7.90 (s, 1H), 7.83 (d, J=4.7Hz, 1H), 7.82 (s, 1H), 7.39 (s, 1H), 7.22-7.33 (m, 4H), 7.85 (s, 2H),2.58 (s, 3H).

Example 43-(1-methyl-1H-pyrazol-4-yl)-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one

Step 1

To a mixture of 5-bromo-3-iodo-6-nitro-1-trityl-1H-indazole (20.0 g,29.5 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyrazole(6.46 g, 29.5 mmol), and PdCl₂(dppf)-CH₂Cl₂ (3.61 g, 4.42 mmol) wereadded degassed dioxane (123 mL) and cesium carbonate (38.3 mL, 2 M, 77mmol). The mixture was purged with nitrogen for 5 min, and heated to 80°C. for 3 h. The mixture was cooled to room temperature, treated withwater, and extracted with DCM (×3). The combined organics were washedwith brine, dried (sodium sulfate), concentrated, and purified by flashchromatography to afford5-bromo-3-(1-methyl-1H-pyrazol-4-yl)-6-nitro-1-trityl-1H-indazole. MS:[M+H]⁺ m/z 564. ¹H NMR (600 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.46 (s, 1H),7.93 (s, 1H), 7.20-7.38 (m, 15H), 6.65 (s, 1H), 3.91 (s, 3H).

Steps 2-3

To a stirred solution of5-bromo-3-(1-methyl-1H-pyrazol-4-yl)-6-nitro-1-trityl-1H-indazole (7.5g, 12.0 mmol) in ethanol (150 mL) was added Zn (1.96 g, 29.9 mmol) andsaturated ammonium chloride solution (50 mL). The mixture was heated to80° C. for 1 h. Additional Zn (2.0 g, 30 mmol) was added and the mixturewas heated to 80° C. for 2 h. The mixture was cooled to roomtemperature, filtered through a pad of Celite, and concentrated. Theresidue was diluted with water and extracted with DCM (×3). The combinedorganics were dried (sodium sulfate), concentrated, and used in the nextstep without further purification. MS: [M+H]⁺ m/z 534.

To a stirred solution of the crude product in THF (31 mL) was addeddiisopropylethylamine (1.2 g, 9.3 mmol) followed by the slow addition ofacryloyl chloride (0.42 g, 4.7 mmol). The mixture was left to stir for 3h, treated with water, and extracted with DCM (×3). The combinedorganics were dried (sodium sulfate), concentrated, and purified byflash chromatography to affordN-[5-bromo-3-(1-methyl-1H-pyrazol-4-yl)-1-trityl-1H-indazol-6-yl]prop-2-enamide.MS: [M+H]⁺ m/z 588. ¹H NMR (600 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.35 (s,1H), 8.29 (s, 1H), 7.84 (s, 1H), 7.22-7.33 (m, 15H), 6.43 (m, 1H), 6.16(d, J=7.0 Hz, 1H), 5.70 (d, J=10.5 Hz, 1H), 3.90 (s, 3H).

Steps 4-5

A mixture ofN-[5-bromo-3-(1-methyl-1H-pyrazol-4-yl)-1-trityl-1H-indazol-6-yl]prop-2-enamide(1.36 g, 2.31 mmol), Pd₂(dba)₃ (0.11 g, 0.12 mmol), tBu₃P-HBF₄ (0.14 g,0.46 mmol), and dicyclohexylmethylamine (0.54 g, 2.8 mmol) in dioxane(33 mL) was purged with nitrogen for 10 min, heated to 100° C.overnight, and cooled to room temperature. The mixture was treated withwater, and extracted with DCM (×3). The combined organics were dried(sodium sulfate), concentrated, and purified by flash chromatography toafford3-(1-methyl-1H-pyrazol-4-yl)-1-trityl-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one.MS: [M+H]⁺ m/z 508.

TFA (0.4 mL) and triethylsilane (0.004 mL, 0.0.02 mmol) were added to astirred solution of3-(1-methyl-1H-pyrazol-4-yl)-1-trityl-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one(20 mg, 0.02 mmol) in DCM (2 mL) and the mixture was stirred at roomtemperature for 2 h. The mixture was concentrated, and purified byprep-HPLC to afford3-(1-methyl-1H-pyrazol-4-yl)-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-onetrifluoroacetate. MS: [M+H]⁺ m/z 266. ¹H NMR (600 MHz, DMSO-d6) δ 12.86(s, 1H), 11.57 (s, 1H), 8.41 (s, 1H), 8.40 (s, 1H), 8.05 (s, 1H), 7.98(d, J=9.6 Hz, 1H), 7.29 (s, 1H), 6.39 (dd, J=9.5, 1.9 Hz, 1H), 3.95 (s,3H).

Example 88-hydroxy-3-(2-methylpyridin-4-yl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinolin-7(8H)-one

Step 1

5-bromo-3-(2-methylpyridin-4-yl)-6-nitro-1-trityl-1H-indazole (72.5 mg,0.19 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (6.0mg, 0.013 mmol) and Pd(OAc)₂ (1.4 mg, 6.3 umol) in THF (1.5 mL) wasdegassed 3 times with N₂/vacuum exchange before(3-ethoxy-3-oxopropyl)zinc(II) bromide (0.38 mL, 0.5 M in THF) was addeddropwise. The mixture was stirred for 5 minutes at room temperature, andthen at 60° C. for 45 minutes. The reaction was quenched with MeOH, themixture was directly purified by column chromatography on silica geleluting with gradient up to EtOAc/isohexane=100% to give ethyl3-(3-(2-methylpyridin-4-yl)-6-nitro-1-trityl-1H-indazol-5-yl)propanoateas light brown syrup.

Step 2

Zinc (107 mg, 1.634 mmol) was added to a stirred mixture ethyl3-(3-(2-methylpyridin-4-yl)-6-nitro-1-trityl-1H-indazol-5-yl)propanoate(65 mg, 0.109 mmol) in acetic acid (1.5 ml) and the mixture was stirredat 60° C. for 2 h. The mixture was cooled and filtered through a celitepad and washed with ethyl acetate. Solvent was removed and the residuewas taken up in ethyl acetate and washed with NaOH (0.1 N) until aqueouslayer basic. The combined organic fractions were washed with water,brine, dried (MgSO₄), filtered and the solvent was evaporated underreduced pressure. The residue was purified by column chromatography onsilica gel eluting with ethyl acetate/hexane gradient up to 80% first,then changed to MeOH/CH₂Cl₂ gradient up to 20% to give8-hydroxy-3-(2-methylpyridin-4-yl)-1-trityl-5,6-dihydro-1H-pyrazolo[4,3-g]quinolin-7(8H)-one.

Step 3

Methanol (9.99 μl, 0.247 mmol) was added to a stirred, mixture of8-hydroxy-3-(2-methylpyridin-4-yl)-1-trityl-5,6-dihydro-1H-pyrazolo[4,3-g]quinolin-7(8H)-one(26.5 mg, 0.049 mmol) in TFA (1 ml) and the mixture was stirred at roomtemperature for 2 h. Solvent was removed and the crude was purified withGilson 0-75% gradient) to give pure8-hydroxy-3-(2-methylpyridin-4-yl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinolin-7(8H)-oneas TFA salt. LCMS: [M+H]+ m/z 295.

Example 93-(2-methylpyridin-4-yl)-5,6,7,9-tetrahydroazepino[3,2-f]indazol-8(1H)-one

Steps 1-2

In a manner similar to that described in Example 8 (Step 1), compound 1Dwas treated with (4-ethoxy-4-oxobutyl)zinc bromide to afford ethyl4-(3-(2-methylpyridin-4-yl)-6-nitro-1-trityl-1H-indazol-5-yl)butanoate(9A).

Zinc (82 mg, 1.253 mmol) was added to a stirred mixture of ethyl4-(3-(2-methylpyridin-4-yl)-6-nitro-1-trityl-1H-indazol-5-yl)butanoate(51 mg, 0.084 mmol) in acetic acid (1.5 ml) and the mixture was stirredat 60° C. for 2 h. The mixture was cooled and filtered through a celitepad and washed with ethyl acetate. Solvent was removed and the residuewas taken up in ethyl acetate and washed with NaOH (0.1 N) until aqueouslayer basic. The combined organic fractions were washed with water,brine, dried (MgSO₄), filtered and the solvent was evaporated underreduced pressure. Ethyl4-(6-amino-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazol-5-yl)butanoatewas obtained and used directly for next step.

Step 3

LHMDS (0.181 ml, 0.181 mmol) was added to a stirred, cooled 0° C.mixture of ethyl4-(6-amino-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazol-5-yl)butanoate(50 mg, 0.086 mmol) in THF (3 ml) and the mixture was stirred at 0° C.for 30 min. TLC (ethyl acetate/hexanes=3/1) showed clean reaction andLCMS clearly showed the product. 0.1 mL of NH₄Cl aqueous solution wasadded to quench the reaction. The mixture was directly purified bycolumn chromatography on silica gel eluting with ethyl acetate/hexanegradient up to 100% first, then changed to MeOH/CH₂Cl₂ gradient up to20% to give3-(2-methylpyridin-4-yl)-1-trityl-5,6,7,9-tetrahydroazepino[3,2-f]indazol-8(1H)-one.

Step 4

Methanol (0.011 ml, 0.281 mmol) was added to a stirred, mixture of3-(2-methylpyridin-4-yl)-1-trityl-5,6,7,9-tetrahydroazepino[3,2-f]indazol-8(1H)-one(30 mg, 0.056 mmol) in TFA (1 ml) and the mixture was stirred at roomtemperature for 2 h. LCMS showed no starting material left. Solvent wasremoved and the crude was purified with Gilson 0-75% gradient) to givepure3-(2-methylpyridin-4-yl)-5,6,7,9-tetrahydroazepino[3,2-f]indazol-8(1H)-oneas TFA salt as light yellow solid. LCMS: [M+H]⁺ m/z 293.

Example 10(R)-6-(1-(4-fluorophenyl)ethyl)-3-(2-methylpyridin-4-yl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one

Step 1

A mixture of5-bromo-3-(2-methylpyridin-4-yl)-6-nitro-1-trityl-1H-indazole (400 mg,0.695 mmol), tetrakis(triphenylphosphine)palladium(0) (80 mg, 0.070mmol) and lithium chloride (88 mg, 2.085 mmol), 1,4-dioxane (3.5 mL),tributyl vinyltin (0.244 mL, 0.834 mmol) and2,6-di-tert-butyl-4-methylphenol (1.532 mg, 6.95 μmol) were degassedwith vacuum/N2 exchanged for 4 times. The resultant mixture was keptstirring at 88° C. for overnight. The crude was cooled and directlypurified by column chromatography on silica gel, eluting with 0%-60%EtOAc/isohexane to provide3-(2-methylpyridin-4-yl)-6-nitro-1-trityl-5-vinyl-1H-indazole.

Step 2

O₃ was bubbled through a solution of3-(2-methylpyridin-4-yl)-6-nitro-1-trityl-5-vinyl-1H-indazole (0.21 g,0.402 mmol) in DCM (5 ml) and MeOH (2.5 ml) at −78° C. for 10 minutes.LCMS and TLC (50% ethyl acetate/hexanes) showed no starting materialleft. N₂ was bubbled through the solution for 5 minutes before Me₂S wasadded (0.3 mL) and the mixture was stirred for 3 hours. The reaction wastaken up in ethyl acetate/NH₄Cl aqueous solution. The organic phases wasdried over Mg₂SO₄, filtered and solvent was removed to give3-(2-methylpyridin-4-yl)-6-nitro-1-trityl-1H-indazole-5-carbaldehyde.

Step 3

(R)-1-(4-Fluorophenyl)ethylamine (33.2 mg, 0.238 mmol) was added to astirred mixture of3-(2-methylpyridin-4-yl)-6-nitro-1-trityl-1H-indazole-5-carbaldehyde (50mg, 0.095 mmol) in DCE (2) and the mixture was stirred at roomtemperature for 10 min. before sodium triacetoxyborohydride (101 mg,0.477 mmol) was added. The mixture was stirred at room temp. overnight.The mixture taken up in ethyl acetate (50 mL), washed with aqueoussodium hydrogen carbonate (saturated, 3×15 mL), dried (MgSO₄), filteredand the solvent was evaporated under reduced pressure to give a mixtureof(R)-1-(4-fluorophenyl)-N-((3-(2-methylpyridin-4-yl)-6-nitro-1-trityl-1H-indazol-5-yl)methyl)ethanamineand an unknown by-product as light yellow foam, which was used as it fornext step.

Step 4

Palladium hydroxide on carbon (20 mg, 0.028 mmol) was added to a stirredmixture of(R)-1-(4-fluorophenyl)-N-((3-(2-methylpyridin-4-yl)-6-nitro-1-trityl-1H-indazol-5-yl)methyl)-ethanamine(65 mg, 0.100 mmol) in EtOH (3 ml) and the mixture was H₂/vacuumexchanged for 3 times and stirred at room temperature overnight. Thereaction was worked up by filtration through a short celite pad andwashed with ethyl acetate. Solvent was removed to give the crude productwhich was used directly for next step.

Step 5

(R)-5-(((1-(4-fluorophenyl)ethyl)amino)methyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazol-6-amine(37.2 mg, 0.060 mmol) was added to a stirred mixture of triphosgene (7.2mg, 0.024 mmol) in dioxane (1.5 ml) and the mixture was stirred at roomtemperature for 45 min. The mixture was quenched with MeOH and NEt₃(drops). The mixture was direct applied to silica gel column elutingwith Hexane/ethyl acetate 100-0%, then ethyl acetate/MeOH 100-70%, togive(R)-6-(1-(4-fluorophenyl)ethyl)-3-(2-methylpyridin-4-yl)-1-trityl-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one.

Step 6

MeOH (1.760 μl, 0.043 mmol) was added to a stirred mixture of(R)-6-(1-(4-fluorophenyl)ethyl)-3-(2-methylpyridin-4-yl)-1-trityl-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one(28 mg, 0.043 mmol) in TFA (1 ml) and the mixture was stirred at roomtemperature for 45 min. The solvent was removed and the crude wasdiluted with DCM and 2M NH3 in MeOH and purified with PTLC (ethylacetate/MeOH=95/5) to give(R)-6-(1-(4-fluorophenyl)ethyl)-3-(2-methylpyridin-4-yl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one.LCMS: [M+H]⁺ m/z 402.

Example 117-(4-fluorobenzyl)-9-hydroxy-3-(2-methylpyridin-4-yl)-5,6,7,9-tetrahydro-[1,3]diazepino[5,4-f]indazol-8(1H)-one

Step 1

The mixture of5-bromo-3-(2-methylpyridin-4-yl)-6-nitro-1-trityl-1H-indazole (400 mg,0.695 mmol), tetrakis(triphenylphosphine)palladium(0) (80 mg, 0.070mmol), lithium chloride (88 mg, 2.085 mmol), allyltributyltin (0.258 ml,0.834 mmol) and 2,6-di-tert-butyl-4-methylphenol (1.532 mg, 6.95 μmol)were degassed with vacuum/N₂ exchanged for 4 times. The resultantmixture was kept stirring at 88° C. for overnight. The crude was cooledand directly purified by column chromatography on silica gel, elutingwith EtOAc/isohexane=0%-60% to give5-allyl-3-(2-methylpyridin-4-yl)-6-nitro-1-trityl-1H-indazole.

Step 2

O₃ was bubbled through a solution of5-allyl-3-(2-methylpyridin-4-yl)-6-nitro-1-trityl-1H-indazole (260 mg,0.485 mmol) in DCM (5 ml) and MeOH (2.5 ml) at −78° C. for 10 minutes,LCMS and TLC (ethyl acetate/hexanes=1/1) showed no starting materialleft. N2 was bubbled through the solution for 5 minutes before Me₂S wasadded (0.3 mL) and the mixture was stirred for 3 hours. The reaction wasworked with with ethyl acetate/NH₄Cl aqueous solution. The organicphases was dried over Mg₂SO₄, filtered and solvent was removed to givecrude2-(3-(2-methylpyridin-4-yl)-6-nitro-1-trityl-1H-indazol-5-yl)acetaldehyde.

Step 3

4-Fluorobenzylamine (65.1 mg, 0.520 mmol) was added to a stirred mixtureof2-(3-(2-methylpyridin-4-yl)-6-nitro-1-trityl-1H-indazol-5-yl)acetaldehyde(140 mg, 0.260 mmol) in DCE (5 ml) and the mixture was stirred at roomtemperature for 10 min. before sodium triacetoxyborohydride (275 mg,1.300 mmol) was added. The mixture was stirred at room temp. overnight.The reaction mixture was directly purified by column chromatography onsilica gel eluting with EtOAc/MeOH gradient from 1% to 30% to giveN-(4-fluorobenzyl)-2-(3-(2-methylpyridin-4-yl)-6-nitro-1-trityl-1H-indazol-5-yl)ethanamine.

Step 4

Palladium hydroxide on carbon (30 mg, 0.043 mmol) was added to a stirredmixture ofN-(4-fluorobenzyl)-2-(3-(2-methylpyridin-4-yl)-6-nitro-1-trityl-1H-indazol-5-yl)ethanamine(96 mg, 0.148 mmol) in ethanol (5 ml) and the mixture was stirred atroom temperature overnight. The reaction was worked up by filtrationthrough a short celite pad and washed with ethyl acetate. The solventwas removed to give the crude which was used directly for next step.

Step 5

Triphosgene (17.57 mg, 0.059 mmol) was added to a stirred mixture ofN-(4-fluorobenzyl)-2-(6-(hydroxyamino)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazol-5-yl)ethanamine(91 mg, 0.148 mmol) in dioxane (3 ml) and the mixture was stirred atroom temperature for 45 min. The reaction was quenched with MeOH andNEt₃ (drops). The mixture was taken up in DCM and washed with NaOH (1N), then was washed with water, and brine, dried (MgSO₄), filtered andthe solvent was evaporated under reduced pressure. The mixture waspurified by PTLC (ethyl acetate/hexanes=4/1) to give to give7-(4-fluorobenzyl)-9-hydroxy-3-(2-methylpyridin-4-yl)-1-trityl-5,6,7,9-tetrahydro-[1,3]diazepino[5,4-f]indazol-8(1H)-one.

Step 6

MeOH (1.717 μl, 0.042 mmol) was added to a stirred mixture of7-(4-fluorobenzyl)-9-hydroxy-3-(2-methylpyridin-4-yl)-1-trityl-5,6,7,9-tetrahydro-[1,3]diazepino[5,4-f]indazol-8(1H)-one(28 mg, 0.042 mmol) in TFA (1 ml) and the mixture was stirred at roomtemperature for 45 min. LCMS and TLC (DCM/MeOH(2M NH₃)=95/5) showed nostarting material left. Solvent was removed and the crude was purifiedwith Gilson (CH₃CN/H₂O/TFA, 10-90% gradient) to give7-(4-fluorobenzyl)-9-hydroxy-3-(2-methylpyridin-4-yl)-5,6,7,9-tetrahydro-[1,3]diazepino-[5,4-f]indazol-8(1H)-oneas the TFA salt. LCMS: [M+H]⁺ m/z 418.

Example 12(R)-7-(1-(4-fluorophenyl)ethyl)-3-(2-methylpyridin-4-yl)-5,6,7,9-tetrahydro-[1,3]diazepino[5,4-f]indazol-8(1H)-one

Steps 1-2

In a manner similar to that described in Example 11 (Step 3),2-(3-(2-methylpyridin-4-yl)-6-nitro-1-trityl-1H-indazol-5-yl)acetaldehydewas reacted with (R)-1-(4-fluorophenyl)ethanamine and sodiumtriacetoxyborohydride to provide(R)-1-(4-fluorophenyl)-N-(2-(3-(2-methylpyridin-4-yl)-6-nitro-1-trityl-1H-indazol-5-yl)ethyl)ethanamine.

Zinc (59.3 mg, 0.907 mmol) was added to a stirred mixture of(R)-1-(4-fluorophenyl)-N-(2-(3-(2-methylpyridin-4-yl)-6-nitro-1-trityl-1H-indazol-5-yl)ethyl)ethanamine(40 mg, 0.060 mmol) in acetic acid (1.5 ml) and the mixture was stirredat 60° C. for 90 min. The mixture was filtered through a short pad ofcelite washing with ethyl acetate and the solvent was removed. Theresidue was taken up in ethyl acetate and washed with aqueous sodiumhydrogen carbonate (saturated, 3×20 mL), water and brine, dried (MgSO₄),filtered and the solvent was evaporated under reduced pressure. Thecrude(R)-5-(2-((1-(4-fluorophenyl)ethyl)amino)ethyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazol-6-aminewas used for next step directly.

Step 3

Triphosgene (6.25 mg, 0.021 mmol) was added to a stirred mixture of(R)-5-(2-((1-(4-fluorophenyl)ethyl)amino)ethyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazol-6-amine(38 mg, 0.060 mmol) in dioxane (2) and the mixture was stirred at roomtemperature for 30 min. The reaction was quenched with MeOH (1 mL)/NEt₃(0.2 mL). The mixture was directly loaded to a silica gel column elutingwith ethyl acetate/Hexane 0-100% gradient and the MeOH/ethyl acetategradient 0-30% to give of (R)-methyl(2-(6-amino-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazol-5-yl)ethyl)(1-(4-fluorophenyl)ethyl)carbamate(16 mg) which was used for next step directly.

Step 4

LHMDS (0.056 ml, 0.056 mmol) was added to a stirred, cooled 0° C.mixture of (R)-methyl(2-(6-amino-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazol-5-yl)ethyl)(1-(4-fluorophenyl)ethyl)carbamate(16 mg, 0.023 mmol) in THF (1.5 ml) and the mixture was heated at 80° C.for 4 days. The mixture was cooled and purified with PTLC (ethylacetate/Hexane=3/2) to give(R)-7-(1-(4-fluorophenyl)ethyl)-3-(2-methylpyridin-4-yl)-1-trityl-5,6,7,9-tetrahydro-[1,3]diazepino[5,4-f]indazol-8(1H)-one.

Step 5

Triethylsilane (0.05 ml) was added to a stirred mixture of(R)-7-(1-(4-fluorophenyl)ethyl)-3-(2-methylpyridin-4-yl)-1-trityl-5,6,7,9-tetrahydro-[1,3]diazepino[5,4-f]indazol-8(1H)-one(3.5 mg, 5.32 μmol) in TFA (0.5 ml) and the mixture was stirred at roomtemperature for 1 h. The solvent was removed and crude was purified bypreparative HPLC Reverse phase (C-18), eluting withAcetonitrile/Water+0.1% TFA10-90% to give(R)-7-(1-(4-fluorophenyl)ethyl)-3-(2-methylpyridin-4-yl)-5,6,7,9-tetrahydro-[1,3]diazepino[5,4-f]indazol-8(1H)-one2,2,2-trifluoroacetate. LCMS: [M+H]⁺ m/z 416.

Example 133-(2-methylpyridin-4-yl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one

Step 1

Palladium hydroxide on carbon (18 mg, 0.026 mmol) was added to a stirredmixture ofN-benzyl-1-(3-(2-methylpyridin-4-yl)-6-nitro-1-trityl-1H-indazol-5-yl)methanamine(50 mg, 0.081 mmol, prepared from 10B and benzylamine as described inExample 10, Step 3) in methanol (2 ml) and DCM (2 ml) and the mixturewas H₂/vacuum exchanged for 3 times and stirred at room temperatureovernight. The reaction was filtered through a short celite pad andwashed with ethyl acetate. Solvent was removed to give the crude(mixture of desired product and over-reduced byproduct) which was useddirectly for next step.

Step 2

Triphosgene (15.58 mg, 0.052 mmol) was added to a stirred mixture of5-((benzylamino)methyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazol-6-amineand 5-(aminomethyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazol-6-amine(41 mg) in dioxane (2.5 ml) and DCM (1.5 ml) and the mixture was stirredat room temperature for 30 min. The reaction was quenched with MeOH (1mL)/NEt₃ (0.2 mL). The mixture was directly loaded to silica gel columneluting with ethyl acetate/Hexane 0-100% gradient and the MeOH/ethylacetate gradient 0-30% to give6-benzyl-3-(2-methylpyridin-4-yl)-1-trityl-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-oneand3-(2-methylpyridin-4-yl)-1-trityl-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one.

Step 3

Et₃SiH (0.05 ml) was added to a stirred mixture of3-(2-methylpyridin-4-yl)-1-trityl-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one(16 mg, 0.031 mmol) in TFA (1 ml) and the mixture was stirred at roomtemperature for 15 minutes. Solvent was removed and crude was purifiedwith preparative HPLC Reverse phase (C-18), eluting withAcetonitrile/Water+0.1% TFA10-90% to give3-(2-methylpyridin-4-yl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one2,2,2-trifluoroacetate. LCMS: [M+H]⁺ m/z 280.

Example 15(R)-3-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-6-(1-phenylethyl)-1H-pyrazolo[4,3-g]quinazoline-5,7(6H,8H)-dione

Step 1

NaH (427 mg, 10.68 mmol) was added to a stirred, room temperaturemixture of methyl 6-chloro-1H-indazole-5-carboxylate (1500 mg, 7.12mmol) in DMF (20 mL) at 0° C. and the mixture was stirred at roomtemperature for 15 min. followed by the addition of N-iodosuccinimide(2403 mg, 10.68 mmol), the mixture was kept stirring at room temp forovernight. The reaction was quenched with slow addition of NH₄Clsolution and EtOAc. The organic phase was washed with saturated Na₂S₂O₃and NaHCO₃ solution, then water and brine. The mixture was dried withMgSO₄ and filtered, washed with ethyl acacate. The mixture was purifiedby column chromatography on silica gel eluting withEtOAc/isohexane=0%-60% to give methyl6-chloro-3-iodo-1H-indazole-5-carboxylate.

Step 2

Sodium hydride (0.357 g, 8.91 mmol) was added to a stirred, cooled 0° C.mixture of methyl 6-chloro-3-iodo-1H-indazole-5-carboxylate (2 g, 5.94mmol) in DMF (30 ml) and the mixture was stirred at 0° C. for 30 min.before (chloromethanetriyl)tribenzene (1.823 g, 6.54 mmol) was added.The mixture was stirred at room temperature overnight. TLC(hexane/EtOAc=6/1) showed 3 spots. The reaction was quenched with NH₄Clsolution and 0.5 M HCl diluted with EtOAc. The mixture was washed withwater (3×50 mL), brine, dried (MgSO₄), filtered and the solvent wasevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel eluting with EtOAc/isohexane gradient from0% to 100% to give methyl6-chloro-3-iodo-1-trityl-1H-indazole-5-carboxylate.

Step 3

1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d][1,2,3]triazole(161 mg, 0.622 mmol), methyl6-chloro-3-iodo-1-trityl-1H-indazole-5-carboxylate (300 mg, 0.518 mmol),sodium bicarbonate (131 mg, 1.555 mmol) in water (2 ml) and1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (85 mg, 0.104 mmol) were mixed in a pressurerelease vial in dioxane (6 mL). The mixture was degassed and backfilledwith nitrogen (3×), dioxane (6 mL) was added, and the resultant mixturewas degassed and backfilled with nitrogen (3×), and heated up to 80° C.in a microwave reactor for 30 minutes. The mixture was cooled, anddirectly purified by column chromatography on silica gel eluting withgradient EtOAc/isohexane=0-80% to give methyl6-chloro-3-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-1-trityl-1H-indazole-5-carboxylate.

Step 4

(R)-1-(1-phenylethyl)urea (53.4 mg, 0.325 mmol), methyl6-chloro-3-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-1-trityl-1H-indazole-5-carboxylate(95 mg, 0.163 mmol), XantPhos Biaryl Precatalyst (28.9 mg, 0.033 mmol),and Cs₂CO₃ (150 mg, 0.49 mmol) in dioxane (2 mL) were mixed in apressure release vial, degassed and backfilled with nitrogen (3×), andheated up to 100° C. for 48 h. The mixture was cooled and loaded tosilica gel column and airpurged for 5 min, then eluted withEtOAc/isohexane=80→100% to give(R)-3-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-6-(1-phenylethyl)-1-trityl-1H-pyrazolo[4,3-g]quinazoline-5,7(6H,8H)-dione.

Step 5

TFA (1.5 ml) and Et₃SiH (0.75 ml) were added to(R)-3-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-6-(1-phenylethyl)-1-trityl-1H-pyrazolo[4,3-g]quinazoline-5,7(6H,8H)-dione(52 mg, 0.076 mmol). The mixture was stirred at room temperature for 15min. Solvent was removed and the crude was purified with gilson reversephase HPLC (C-8), eluting with Acetonitrile/Water+0.1% TFA10-90% to give(R)-3-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-6-(1-phenylethyl)-1H-pyrazolo[4,3-g]quinazoline-5,7(6H,8H)-dione2,2,2-trifluoroacetate as a light yellow solid. LCMS: [M+H]⁺ m/z 438.

Example 24 3-morpholino-1H-pyrazolo[4,3-g]quinolin-7(8H)-one

Step 1

To a suspension of 5-bromo-6-nitro-1H-indazole (2.00 g, 8.26 mmol) inEtOH (20 ml) was added sodium hypochlorite (11.77 ml, 24.79 mmol)dropwise in one portion. LC showed complete conversion at rt after 15min. The reaction was quenched with 10% Na₂SO₃ (20 mL) and stirredovernight. The mixture was then diluted with water (80 mL), extractedwith EtOAc (50 mL×3), washed with brine, dried over Na₂SO₄, andconcentrated to give 5-bromo-3-chloro-6-nitro-1H-indazole the crudeproduct which was used without further purification.

Steps 2-3

In a manner similar to that described in Example 1 (Step 2),5-bromo-3-chloro-6-nitro-1H-indazole was treated with TrCl and NaH toprovide 5-bromo-3-chloro-6-nitro-1-trityl-1H-indazole.

To a solution of provide 5-bromo-3-chloro-6-nitro-1-trityl-1H-indazole(5.0 g, 9.64 mmol) in MeOH (25 ml) and DCM (25 ml) was added 3% Pt oncarbon doped with 0.6% V (1.880 g) and the resulting mixture was stirredunder a hydrogen balloon for 6 h. The reaction mixture was diluted with25 mL of DCM and filtered through a celite pad and washed withadditional DCM. After concentrating the filtrate down to about 15 mLleft (mainly MeOH), precipitation occurred. The precipitates werefiltered and washed with MeOH to give5-bromo-3-chloro-1-trityl-1H-indazol-6-amine.

Steps 4-5

In a manner similar to that described in Example 4 (Steps 3-4),5-bromo-3-chloro-1-trityl-1H-indazol-6-amine was treated sequentiallywith acryloyl chloride (Hunig's base, THF) and then Pd₂(dba)₃,(tBu₃P—HBF₄, dicyclohexylmethylamine) to give3-chloro-1-trityl-1H-pyrazolo[4,3-g]quinolin-7(8H)-one.

Steps 6-7

In a 1 dram vial was added morpholine (1.4 mg, 0.016 mmoles, 1.5 eq.),and sodium t-butoxide (3.12 mg, 0.032 mmol, 3 eq). In a second 1 dramvial was added3-chloro-1-trityl-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one (5 mg,10.82 μmol) with Ruphos pre-catalyst(chloro-(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]-palladium(II)),0.158 mg, 0.216 μmol) dissolved in 0.5 mL of degassed THF (from nitrogengas over 45 minutes). This solution was dispensed (0.5 mL each) into thefirst 1 dram vial. The vial was purged with nitrogen gas, sealed with astir bar, and were heated at 65° C. for 16 hours. The solvent wasremoved and the product were purified by semi-preparative RP-HPLC togenerate the pure title compound3-morpholino-1-trityl-1H-pyrazolo[4,3-g]quinolin-7(8H)-one (LCMS: [M+H]⁺m/z 513)

In a 1 dram vial containing the aforementioned product3-morpholino-1-trityl-1H-pyrazolo[4,3-g]quinolin-7(8H)-one, 0.5 mL ofDCM, 0.5 mL TFA and 10 uL of triethylsilane were added and the vial wasstirred at room temperature for 2 hours. 0.5 mL of water was added afterthis time and the solvents were removed in vacuo. Analytical LC/MSanalysis indicated that the deprotection of the trityl group wascomplete. The solvents were removed in vacuo and lyophilized fromwater/ACN to obtain 3-morpholino-1H-pyrazolo[4,3-g]quinolin-7(8H)-one.LCMS: [M+H]⁺ m/z 271.

Example 26(R)-3-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one

Step 1

Sodium hypochlorite (21.54 mL, 13.96 mmol) was added to a stirred, roomtemperature mixture of 6-nitro-5-vinyl-1H-indazole 26A (2.2 g, 11.63mmol, prepared from 5-bromo-6-nitro-1H-indazole andtributyl(vinyl)stannane as described in Example 10, Step 1) indichloromethane (100 mL) and the mixture was stirred at room temperatureovernight. The mixture was diluted with dichloromethane (6 mL), washedwith water (2 mL), dried (MgSO₄), filtered and the solvent wasevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel (24 g), eluting with EtOAc/isohexane=10% togive 3-chloro-6-nitro-5-vinyl-1H-indazole (26B). MS ESI calc'd. forC₉H₆ClN₃O₂ [M+H]⁺ 224, found 224.

Step 2

Triphenylmethyl chloride (2.54 g, 9.12 mmol) was added to a stirred,room temperature mixture of 3-chloro-6-nitro-5-vinyl-1H-indazole (1.7 g,7.60 mmol) and Hunig's Base (2.66 mL, 15.20 mmol) in dichloromethane (40mL), and the mixture was stirred at room temperature for overnight. Themixture was concentrated, the residue was purified by columnchromatography on silica gel (24 g), eluting with EtOAc/isohexane=10% togive 3-chloro-6-nitro-1-trityl-5-vinyl-1H-indazole (26C).

Step 3

Ozone (0.340 g, 7.08 mmol) was bubbled into a stirred, −78° C. mixtureof 3-chloro-6-nitro-1-trityl-5-vinyl-1H-indazole (3.3 g, 7.08 mmol) indichloromethane (50 mL) and MeOH (25 mL) till the mixture turnedgreenish blue, indicating the excess of ozone. Nitrogen was then blowninto the mixture to remove the excess of ozone. When the color changedfrom greenish blue to yellow, dimethyl sulfide (5.18 mL, 70.8 mmol) wasadded, and the mixture was stirred at room temperature for 1 h. Themixture was concentrated, the residue was diluted with ethyl acetate (60mL), washed with aqueous ammonium chloride (saturated, 1×30 mL), andwater (3×30 mL), dried (MgSO₄), filtered and the solvent was evaporatedunder reduced pressure to give3-chloro-6-nitro-1-trityl-1H-indazole-5-carbaldehyde (26D).

Step 4

Sodium triacetoxyborohydride (1.699 g, 8.01 mmol) was added to astirred, room temperature mixture of (R)-(+)-1-phenyl ethylamine (0.818mL, 6.41 mmol) and 3-chloro-6-nitro-1-trityl-1H-indazole-5-carbaldehyde(1.5 g, 3.21 mmol) in dichloroethane (30 mL), and the mixture wasstirred at room temperature. Reaction was monitored via LCMS, 1 h, 6 h,and overnight. The mixture was directly loaded onto the column (120 g,silica gel), the column was purged with air for 5 min and eluted withEtOAc/isohexane=10% to give(R)—N-((3-chloro-6-nitro-1-trityl-1H-indazol-5-yl)methyl)-1-phenylethanamine(26E). MS ESI calc'd. for C₃₅H₂₉ClN₄O₂ [M+H]⁺ 573, found 573.

Step 5

Zinc (0.570 g, 8.72 mmol) was added to a stirred, room temperaturemixture of(R)—N-((3-chloro-6-nitro-1-trityl-1H-indazol-5-yl)methyl)-1-phenylethanamine(0.5 g, 0.872 mmol) in acetic acid (88 mL,) and the mixture was stirredat 60° C. for 1 h. LCMS check, completed, starting material disappeared.The mixture was filtered through Celite, washed with MeOH, the filtratewas concentrated. The residue was diluted with dichloromethane (5 mL),water (1 mL) was added, the aqeuous layer was basified with aqueoussodium hydrogen carbonate saturated to pH 9, extracted withdichloromethane (2×3 mL), the combined organic was dried MgSO₄, filteredand concentrated, the residue was purified by column chromatography onsilica gel (40 g), eluted with EtOAc/isohexane=1:2 to give(R)-3-chloro-5-(((1-phenylethyl)amino)methyl)-1-trityl-1H-indazol-6-amine(26F). MS ESI calc'd. for C₃₅H₃₁ClN₄ [M+H]⁺ 543, found 543.

Step 6

Triphosgene (43.7 mg, 0.147 mmol) was added to a stirred, roomtemperature mixture of(R)-3-chloro-5-(((1-phenylethyl)amino)methyl)-1-trityl-1H-indazol-6-amine(200 mg, 0.368 mmol) in dichloromethane (3 mL) and the mixture wasstirred at room temperature for overnight. The mixture was diluted withdichloromethane (5 mL), washed with aqueous sodium hydrogen carbonate(saturated, 1×6 mL), dried (MgSO₄), filtered and the solvent wasevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel (40 g), eluting with EtOAc/isohexane=1:3 togive(R)-3-chloro-6-(1-phenylethyl)-1-trityl-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one(26G). MS ESI calc'd. for C₃₆H₂₉ClN₄O [M+H]⁺ 569, found 569.

Step 7

1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d][1,2,3]triazole(27.3 mg, 0.105 mmol),(R)-3-chloro-6-(1-phenylethyl)-1-trityl-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one(50 mg, 0.088 mmol), Xphos-Pd-Precatalyt-G2 (17 mg, 0.022 mmol) andpotassium phosphate tribasic (55.9 mg, 0.264 mmol) were mixed in apressure release vial, degassed and backfilled with nitrogen (3×),dioxane (3 mL) and water (1 mL) were added, the resultant mixture wasdegassed and backfilled with nitrogen (3×) again, and heated up to 80°C. for 3 h. LCMS check, completed, starting material disappeared. Themixture was cooled, the mixture was diluted with dichloromethane (10 mL)and water (3 mL), filtered through celite, organic layer was separatedand washed with brine (5 mL), dried (MgSO₄), filtered and the solventwas evaporated under reduced pressure. The residue was purified bycolumn chromatography on silica gel (24 g), eluting withEtOAc/isohexane=30%→100% to give(R)-3-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-6-(1-phenylethyl)-1-trityl-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one(26H). MS ESI calc'd. for C₄₃H₃₅N₇O [M+H]⁺ 666, found 666.

Step 8

Triethylsilane (50 μL, 0.313 mmol) was added to a stirred, roomtemperature mixture of(R)-3-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-6-(1-phenylethyl)-1-trityl-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one(50 mg, 0.075 mmol) in TFA (2 mL, 26.0 mmol) and the mixture was stirredat room temperature for 2 h. The mixture was concentrated, and theresidue was purified by preparative HPLC Reverse phase (C-18), elutingwith Acetonitrile/water+0.1% TFA, to give(R)-3-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one2,2,2-trifluoroacetate (26). MS ESI calc'd. for C₂₄H₂₁N₇O [M+H]⁺ 424,found 424.

Example 29(R)-3-(ethylamino)-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one

Steps 1-2

In the reaction vessel ethyl amine (2M in THF) (0.079 mL, 0.158 mmol)and(R)-3-chloro-6-(1-phenylethyl)-1-trityl-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one7 (60 mg, 0.105 mmol) were combined, followed by Brettphos palladacycle(16.84 mg, 0.021 mmol). This mixture was then evacuated and backfilledwith N₂ (3 times). Then dry, degassed dioxane (1 mL) and potassiumtert-butoxide (1M in THF) (0.316 mL, 0.316 mmol) was added to themixture. This mixture was then evacuated and backfilled with N₂ (3times), then heated at 80° C. for 4 h. LCMS check, completed, startingmaterial disappeared. The reaction mixture was loaded directly onto a 40g silica column, airpurged for 10 min, then eluted withEtOAc/isohexane=30%→80% to give(R)-3-(ethylamino)-6-(1-phenylethyl)-1-trityl-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one.MS ESI calc'd. for C₃₈H₃₅N₅O [M+H]⁺ 578, found 578.

In a manner similar to that previously described (e.g. Example 26, Step8),(R)-3-(ethylamino)-6-(1-phenylethyl)-1-trityl-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-onewas deprotected with TFA and triethylsilane to provide(R)-3-(ethylamino)-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one.MS ESI calc'd. for C₁₉H₂₁N₅O [M+H]⁺ 336, found 336.

Examples 30 and 316-((R)-1-phenylethyl)-3-(((S)-1,1,1-trifluoropropan-2-yl)amino)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-oneand(R)-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3-g]-quinazolin-7(8H)-one

Steps 1-2

In the reaction vessel (S)-1,1,1-trifluoroisopropylamine hydrochloride(23.65 mg, 0.158 mmol) and(R)-3-chloro-6-(1-phenylethyl)-1-trityl-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one(26G, 60 mg, 0.105 mmol) were combined, followed by Brettphospalladacycle (16.84 mg, 0.021 mmol). This mixture was then evacuated andbackfilled with N₂ (3 times). Then dry, degassed dioxane (1 mL) andpotassium tert-butoxide (1M in THF) (0.316 mL, 0.316 mmol) was added tothe mixture. This mixture was then evacuated and backfilled with N₂ (3times), then heated at 80° C. for 12 h. LCMS check, completed, startingmaterial disappeared. The reaction mixture was loaded directly onto a 40g silica gel column, airpurged for 10 min, then eluted withEtOAc/isohexane=30%→60% to give mixture of6-((R)-1-phenylethyl)-3-(((S)-1,1,1-trifluoropropan-2-yl)amino)-1-trityl-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one30A and(R)-6-(1-phenylethyl)-1-trityl-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one31A.

Triethylsilane (50 μL, 0.313 mmol) was added to a stirred, roomtemperature mixture of 30A and 31A (65 mg, 0.101 mmol) in TFA (2 mL,26.0 mmol) and the mixture was stirred at room temperature for 2 h. LCMScheck, completed, starting material disappeared. The mixture wasconcentrated to dryness, and the residue was purified by preparativeHPLC Reverse phase (C-18), eluting with Acetonitrile/water+0.1% TFA, togive6-((R)-1-phenylethyl)-3-(((S)-1,1,1-trifluoropropan-2-yl)amino)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one2,2,2-trifluoroacetate (30), MS ESI calc'd. C₂₀H₂₀F₃N₅O [M+H]⁺ 404,found 404; and(R)-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one2,2,2-trifluoroacetate (31), MS ESI calc'd. for C₁₇H₁₆N₄O [M+Na]⁺ 315,found 315 [M+Na].

Example 32(R)-3-amino-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one

Step 1

In the reaction vessel 2,4-dimethoxybenzylamine (66.1 mg, 0.395 mmol)and(R)-3-chloro-6-(1-phenylethyl)-1-trityl-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one(26G, 150 mg, 0.264 mmol) were combined, followed by Brettphospalladacycle (42.1 mg, 0.053 mmol). This mixture was then evacuated andbackfilled with N₂ (3 times). Then dry, degassed dioxane (2 mL) andpotassium tert-butoxide (1M in THF) (0.791 mL, 0.791 mmol) was added tothe mixture. This mixture was then evacuated and backfilled with N₂ (3times), then heated at 80° C. for overnight. LCMS check, completed,starting material disappeared. The reaction mixture was loaded directlyonto a 40 g silica column, airpurged for 10 min, and then eluted withEtOAc/isohexane=30-80% to give(R)-3-((2,4-dimethoxybenzyl)amino)-6-(1-phenylethyl)-1-trityl-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one(32A). MS ESI calc'd. C₄₅H₄₁N₅O₃ [M+H]⁺ 700, found 700.

Step 2

Triethylsilane (25 μL, 0.157 mmol) was added to a stirred, roomtemperature mixture of(R)-3-((2,4-dimethoxybenzyl)amino)-6-(1-phenylethyl)-1-trityl-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one(32A, 45 mg, 0.064 mmol) in TFA (1 mL, 12.98 mmol) and the mixture wasstirred at room temperature for 2 h. The mixture was concentrated, andthe residue was purified by preparative HPLC Reverse phase (C-18),eluting with Acetonitrile/water+0.1% TFA, to give(R)-3-amino-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one2,2,2-trifluoroacetate. MS ESI calc'd. C₁₇H₁₇N₅O [M+H]⁺ 308, found308.00

Example 33 (R)-methyl(7-oxo-6-(1-phenylethyl)-5,6,7,8-tetrahydro-1H-pyrazolo[4,3-g]quinazolin-3-yl)carbamate

Steps 1-2

Methyl chloroformate (6.64 μL, 0.086 mmol) was added to a stirred, roomtemperature mixture of(R)-3-((2,4-dimethoxybenzyl)amino)-6-(1-phenylethyl)-1-trityl-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one(32A, 40 mg, 0.057 mmol) and pyridine (100 μL, 1.236 mmol) indichloromethane (1 mL) and the mixture was stirred at room temperaturefor overnight. The residue was loaded directly onto a 24 g silica gelcolumn, airpurged for 10 min., and then eluted with EtOAc/isohexane=2:1,to give (R)-methyl2,4-dimethoxybenzyl(7-oxo-6-(1-phenylethyl)-1-trityl-5,6,7,8-tetrahydro-1H-pyrazolo[4,3-g]quinazolin-3-yl)carbamate.MS ESI calc'd. C₄₇H₄₃N₅O₅ [M+H]⁺ 758, found 758.

In a manner similar to that previously described (e.g. Example 32, Step2), (R)-methyl2,4-dimethoxybenzyl(7-oxo-6-(1-phenylethyl)-1-trityl-5,6,7,8-tetrahydro-1H-pyrazolo[4,3-g]quinazolin-3-yl)carbamatewas deprotected with TFA and triethylsilane to provide (R)-methyl(7-oxo-6-(1-phenylethyl)-5,6,7,8-tetrahydro-1H-pyrazolo[4,3-g]quinazolin-3-yl)carbamate.MS ESI calc'd. for C₁₉H₂₁N₅O [M+H]⁺ 366, found 366.

Example 35

Step 1

In a flask fitted with a reflux condenser under an atmosphere ofnitrogen gas, 5-bromo-6-nitro-1H-indazole (6.01 g, 24.83 mmol) wasdissolved in a solution of dioxane (100 ml)/water (50 ml) andvinylboronic acid dibutyl ester (8.21 ml, 37.2 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium(ii)dichloridedichloromethane complex (2.332 g, 2.86 mmol) followed by potassiumphosphate (16.87 g, 79 mmol) were added. The resulting mixture washeated to 80° C. and stirred overnight. The mixture was diluted withdichloromethane (400 mL) and basified with aqueous sodium hydrogencarbonate (500 mL) to pH 8. The biphasic solution was separated and theaqueous layer was extracted with dichloromethane (2×500 mL). Thecombined organic phase was dried over sodium sulfate, filtered andconcentrated to dryness under reduced pressure. Column chromatographicpurification (220 g silica column, 5-75% ethyl acetate/hexanes) provided6-nitro-5-vinyl-1H-indazole (26A).

Step 2

In a flask, under an atmosphere of nitrogen gas,6-nitro-5-vinyl-1H-indazole (1.65 g, 8.72 mmol) was dissolved in THF (50ml). The reaction mixture was treated with 1.0 M solution of sodiumbis(trimethylsilyl)amide in tetrahydrofuran (21.81 ml) and stirred atroom temperature for 30 minutes before the addition of N-iodosuccinimide(3.53 g, 15.70 mmol). The resulting reaction was stirred at roomtemperature overnight. The mixture was diluted with dichloromethane (150mL) and basified with aqueous sodium hydrogen carbonate (150 mL) to pH8. The biphasic solution was separated and the aqueous layer wasextracted with dichloromethane (2×150 mL). The combined organic phasewas dried over sodium sulfate, filtered and concentrated to provide3-iodo-6-nitro-5-vinyl-1H-indazole (35B).

Steps 3-7

In a manner similar to that described in Example 26 (Step 2-4),3-iodo-6-nitro-5-vinyl-1H-indazole was sequentially treated with tritylchloride (Hunig's base, DCM), ozone (MeOH-DCM) and (R)-(+)-1-phenylethylamine (sodium triacetoxyborohydride, dichloroethane) to provide3-iodo-6-nitro-1-trityl-5-vinyl-1H-indazole 35E.

In a manner similar to that described in Example 24 (Step 3) and Example26 (Step 6), respectively, 3-iodo-6-nitro-1-trityl-5-vinyl-1H-indazolewas sequentially hydrogenated (1 atm H₂, 3% Pt/0.6% V on carbon,MeOH-DCM) and then treated with triphosgene to provide(R)-3-iodo-6-(1-phenylethyl)-1-trityl-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one35F

Steps 8-9

(R)-3odo-6-(1-phenylethyl)-1-trityl-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one(14 mg, 0.021 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (35F, 5.01mg, 0.021 mmol), cesium carbonate (20.72 mg, 0.064 mmol), copper(I)iodide (2.018 mg, 10.60 μmol) and methanol (500 μl, 12.48 mmol) werecombined in a microwave vial. This mixture was then microwaved for 20minutes at 140° C. The mixture was diluted with water and then extractedwith DCM. The combined organic layers were filtered through celite,concentrated, and purified by column chromatography (12 g, 0-50%EtOAc/hexanes) to give(R)-3-methoxy-6-(1-phenylethyl)-1-trityl-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one.

In a manner similar to that described earlier (e.g. Example 26, Step 8)(R)-3-methoxy-6-(1-phenylethyl)-1-trityl-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-onewas treated with TFA and Et₃SiH to provide(R)-3-methoxy-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one(35). LCMS: [M+H]⁺ m/z 323.

Example 386-((R)-1-phenylethyl)-3-((tetrahydrofuran-3-yl)oxy)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one

In a manner similar to that described Example 35,(R)-3-iodo-6-(1-phenylethyl)-1-trityl-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one(35F) was reacted with tetrahydrofuran-3-ol (Cs₂CO₃, CuI,3,4,7,8-tetramethyl-1,10-phenanthroline) with toluene (0.076M) added asa solvent (microwaved 20 min at 150° C.). The resulting product waschromatographed and then treated with TFA and Et₃SiH to provide6-((R)-1-phenylethyl)-3-((tetrahydrofuran-3-yl)oxy)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one(38). LCMS: [M+H]⁺ m/z 379.

Example 40(R)-3-cyclopropyl-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one

To a vial were added(R)-3-iodo-6-(1-phenylethyl)-1-trityl-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one(35F, 0.02 g, 0.030 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium(ii)dichloridedichloromethane complex (4.95 mg, 6.06 μmol),2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.18 mg, 0.061mmol), potassium carbonate (10.46 mg, 0.076 mmol), dioxane (1 ml) andwater (0.5 ml). The mixture was Vac/N2 purged 6 times and heated at 70°C. for 4 h. The mixture was diluted with DCM (5 mL). The organic phasewas separated and filtered to afford(R)-3-cyclopropyl-6-(1-phenylethyl)-1-trityl-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one.

The solid was treated with trifluoroacetic acid (500 μl, 6.49 mmol) andtriethylsilane (10 μl, 0.063 mmol) and stirred overnight at roomtemperature. The reaction was then concentrated and purified bypreparative HPLC (Reverse phase C-18, Waters SunFire PrepODB, 150×19 mm,5 u, eluting with 10-95% Acetonitrile/Water+0.1% TFA, 20 mL/min. over 15min.) to give(R)-3-cyclopropyl-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one-TFAsalt (40). (TFA salt). LCMS: [M+H]⁺ m/z 333.

Example 42(R)-3-morpholino-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one

A flask was charged with(R)-3-iodo-6-(1-phenylethyl)-1-trityl-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one(35F, 0.02 g, 0.030 mmol), copper(I) iodide (1 mg, 5.25 μmol), L-proline(2 mg, 0.017 mmol) and potassium carbonate (4.18 mg, 0.030 mmol). DMSO(1514 μl) and morpholine (5.28 μl, 0.061 mmol) were added and thereaction was degassed (vacuum/nitrogen). The mixture was heated at 70°C. for 4 h, at which time additional CuI (2 mg), L-proline (2 mg, 0.017mmol), and morpholine (12 uL) were added. The mixture was then heated at90° C. overnight, cooled and then diluted with DCM and water. The layerswere separated and the aqueous layer was extracted with DCM. Thecombined organic layers were filtered through celite and concentrated.Purification by column chromatography on silica gel (12 g, eluting with0-40% EtOAc/hexanes) gave(R)-3-morpholino-6-(1-phenylethyl)-1-trityl-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one.LCMS: [M+H]⁺ m/z 620.

The residue was treated with trifluoroacetic acid (500 μl, 6.49 mmol)and triethylsilane (10 μl, 0.063 mmol) and then stirred overnight atroom temperature. The mixture was concentrated. The residue was purifiedby column chromatography on silica gel (4 g, eluting with 100% EtOAc) togive(R)-3-morpholino-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one(42). LCMS: [M+H]⁺ m/z 378.

Example 44(R)-3-amino-6-(1-phenylethyl)-1H-pyrazolo[4,3-g]quinazoline-5,7(6H,8H)-dione

Step 1

Brettphos palladacycle (41.4 mg, 0.052 mmol), K₃PO₄ (220 mg, 1.037mmol), benzyl carbamate (104 mg, 0.691 mmol) and methyl6-chloro-3-iodo-1-trityl-1H-indazole-5-carboxylate (200 mg, 0.346 mmol)were mixed toluene (3.5 ml) in a pressure release vial, degassed andbackfilled with nitrogen (3×), and heated up to 78° C. for 16 h. Themixture was cooled and loaded onto a 40 g silica column, airpurged for 5min, then eluted with EtOAc/isohexane=80→100% to give methyl3-(((benzyloxy)carbonyl)amino)-6-chloro-1-trityl-1H-indazole-5-carboxylate(44A).

Steps 2-3

In a manner similar to that described in Example 15 (Step 3),(R)-1-(1-phenylethyl)urea (21.82 mg, 0.133 mmol), methyl3-(((benzyloxy)carbonyl)amino)-6-chloro-1-trityl-1H-indazole-5-carboxylate(40 mg, 0.066 mmol), XantPhos Biaryl Precatalyst (11.81 mg, 0.013 mmol),cesium carbonate (64.9 mg, 0.199 mmol) in dioxane (1 mL) were mixed in apressure release vial, degassed and backfilled with nitrogen (3×), andthe mixture was heated up to 100° C. for 24 h. The mixture was cooledand loaded onto a 40 g silica gel column, airpurged for 5 min, theneluted with EtOAc/isohexane=80→100% to give(R)-3-amino-6-(1-phenylethyl)-1-trityl-1H-pyrazolo[4,3-g]quinazoline-5,7(6H,8H)-dione(44B).

In a manner similar to that described in Example 15 (Step 4),(R)-3-amino-6-(1-phenylethyl)-1-trityl-1H-pyrazolo[4,3-g]quinazoline-5,7(6H,8H)-dionewas treated with TFA and Et₃SiH to provide(R)-3-amino-6-(1-phenylethyl)-1H-pyrazolo[4,3-g]quinazoline-5,7(6H,8H)-dione2,2,2-trifluoroacetate (44). LCMS: [M+H]⁺ m/z 322.

Example 45(R)-3-(2-methylpyridin-4-yl)-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[3′,4′:5,6]-pyrido-[3,2-d]pyrimidin-7(8H)-one

Step 1

Into a 500-mL round-bottom flask was placed a solution of5-bromo-2-methylpyridin-3-amine (45A, 20 g, 107 mmol, 1.00 equiv) andN-bromosuccinimide (20 g, 112 mmol, 1.05 equiv) in acetonitrile (200mL). After stirring for 2 h at 25° C., the reaction mixture was quenchedby the addition of water (200 mL) and then extracted withdichloromethane (300 mL×3). The combined organic layers were washed withbrine (200 mL×2), and dried over anhydrous sodium sulfate. Uponfiltration and concentration under vacuum, the crude product waspurified by a flash chromatography on a silica gel column eluting withethyl acetate/petroleum ether (1:3) to afford5,6-dibromo-2-methylpyridin-3-amine (45B). ¹H-NMR (300 MHz, DMSO-d₆): δppm 7.25 (s, 1H), 5.53 (s, NH), 2.20 (s, 3H). MS m/z [M+H]⁺ (ESI): 266.

Step 2

Into a 1000-mL round-bottom flask was placed a mixture of5,6-dibromo-2-methylpyridin-3-amine (28 g, 105.29 mmol, 1.00 equiv),acetic anhydride (42.9 g, 420.22 mmol, 4.00 equiv) and KOAc (12.4 g,126.53 mmol, 1.20 equiv) in chloroform (500 mL). After stirring thereaction for 3 h at 25° C. and 2 h at reflux, isoamylnitrite (29.8 mL,305.64 mmol, 1.00 equiv) and 18-crown-6 (2.5 g, 9.47 mmol, 0.10 equiv)were added at ambient temperature. The reaction mixture was heated for 8h at reflux. After cooling the reaction to room temperature, methanol(100 ml) and a solution of potassium carbonate (29.0 g) in water (200ml) were added. The resulting mixture was stirred for 3 h at 25° C. andextracted with ethyl acetate (500 mL×3). The combined organic layerswere dried over anhydrous sodium sulfate. After filtration andconcentration under vacuum, the residue was purified by a flashchromatography on silica gel column eluting with ethyl acetate/petroleumether (1:3) to afford 5,6-dibromo-1H-pyrazolo[4,3-b]pyridine (45C).¹H-NMR (300 MHz, DMSO-d₆): δ ppm 8.52 (s, 1H), 8.30 (s, 1H). MS m/z[M+H]⁺ (ESI): 277.

Step 3

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of5,6-dibromo-1H-pyrazolo[4,3-b]pyridine (10.0 g, 36.11 mmol, 1.00 equiv),tetrakis(triphenylphosphine)palladium (4.17 g, 3.61 mmol, 0.10 equiv),tributyl(ethenyl)stannane (12.68 g, 39.99 mmol, 1.10 equiv) inN,N-dimethylformamide (50 mL). After stirring overnight at 100° C. andcooling to room temperature, the reaction mixture was diluted with water(500 mL) and extracted with ethyl acetate (500 mL×3). The combinedorganic layers were washed with brine (500 mL×3) and dried overanhydrous sodium sulfate. After filtration and concentration undervacuum, the residue was purified by a flash chromatography on silica gelcolumn eluting with ethyl acetate/petroleum ether (1:30-1:10) to afford6-bromo-5-ethenyl-1H-pyrazolo[4,3-b]pyridine (45D). MS m/z [M+H]⁺ (ESI):226.

Step 4

Into a solution of 6-bromo-5-ethenyl-1H-pyrazolo[4,3-b]pyridine (1.9 g,8.48 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL) was added sodiumhydride (370 mg, 60%, 15.42 mmol, 1.10 equiv) at 0° C. After stirringthe reaction for 30 min at 0-10° C., SEM-Cl (2.1 g, 12.65 mmol, 1.50equiv) was added. The resulting mixture was stirred overnight at roomtemperature, quenched with water (300 mL) and extracted with ethylacetate (200 mL×3). The combined organic layers were washed with brine(200 mL×3) and dried over anhydrous sodium sulfate. After filtration andconcentration under vacuum, the residue was purified by a flashchromatography on silica gel column eluting with ethyl acetate/petroleumether (1:100-1:50) to afford6-bromo-5-ethenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazolo-[4,3-b]-pyridine(45E). MS m/z [M+H]⁺ (ESI): 356.

Step 5

Into a 20-mL sealed tube purged and maintained with an inert atmosphereof nitrogen, was placed a mixture of6-bromo-5-ethenyl-1-[[2-(trimethylsilyl)ethoxy]-methyl]-1H-pyrazolo[4,3-b]pyridine(1.90 g, 5.36 mmol, 1.00 equiv), tert-butyl carbamate (940 mg, 8.02mmol, 1.50 equiv), Xantphos (310 mg, 0.54 mmol, 0.10 equiv), cesiumcarbonate (4.37 g, 13.41 mmol, 2.50 equiv), Pd₂(dba)₃ (280 mg, 0.27mmol, 0.05 equiv) in dioxane (20 mL). After stirring for 4 h at 100° C.and cooling to room temperature, the reaction mixture was diluted withwater (200 mL) and extracted with ethyl acetate (200 mL×3). The combinedorganic layers were washed with brine. (200 mL×3) and dried overanhydrous sodium sulfate. After filtration and concentrated undervacuum, the residue was purified by a flash chromatography on silica gelcolumn eluting with ethyl acetate/petroleum ether (1:30-1:10) to affordtert-butylN-(5-ethenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazolo[4,3-b]pyridin-6-yl)carbamate(45F). MS m/z [M+H]⁺ (ESI): 391.

Step 6

Into a 50-mL round-bottom flask, was placed tert-butylN-(5-ethenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazolo[4,3-b]pyridin-6-yl)carbamate(280 mg, 0.72 mmol, 1.00 equiv), sodium periodate (768 mg, 3.59 mmol,5.00 equiv), osmium tetroxide (0.2 ml, 20 mg/mL in THF) in THF/H₂O(20:1) (21 mL). After stirring for 2 h at ambient temperature, thereaction mixture was diluted with water (50 mL) and extracted with ethylacetate (100 mL×3). The combined organic layers were washed with brine(100 mL×3) and dried over anhydrous sodium sulfate. Filtration andconcentration under vacuum afforded tert-butylN-(5-formyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazolo[4,3-b]pyridin-6-yl)carbamate(45G). ¹H-NMR (400 MHz, CDCl₃): δ ppm 10.46 (s, 1H), 10.16 (s, 1H), 9.01(s, 1H), 8.35 (s, 1H), 5.75 (s, 2H), 3.64-3.60 (m, 2H), 1.60 (s, 9H),096-0.92 (m, 2H), 0.02 (s, 9H). MS m/z [M+H]⁺ (ESI): 393.

Step 7

Into a solution of tert-butylN-(5-formyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazolo[4,3-b]pyridin-6-yl)carbamate(200 mg, 0.51 mmol, 1.00 equiv) and acetic acid (0.5 mL, 1.00 equiv) in1,2-dichloroethane (5 mL) was added (1R)-1-phenylethan-1-amine (309 mg,2.55 mmol, 5.00 equiv) at ambient temperature. After stirring for 1 h,methanol (10 mL) and sodium borohydride (58 mg, 1.53 mmol, 3.00 equiv)were added. The resulting mixture was stirred for 1 h at ambienttemperature, quenched with sat. NaHCO₃ (100 mL) and extracted with ethylacetate (100 mL×3). The combined organic layers were washed with brine(100 mL×3) and dried over anhydrous sodium sulfate. Upon filtration andconcentration under vacuum, the residue was purified by a flashchromatography on silica gel column eluting with ethyl acetate/petroleumether (1:30-1:10) to afford tert-butylN-[5-([[(1R)-1-phenylethyl]amino]methyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazolo[4,3-b]pyridin-6-yl]carbamate(45H) as a white solid. ¹H-NMR (400 MHz, CDCl₃): δ ppm 10.50 (s, NH),8.59 (s, 1H), 8.09 (s, 1H), 7.46-7.29 (m, 5H), 5.72 (s, 2H), 4.18-4.12(s, 2H), 4.08 (m, 1H),3.64-3.60 (m, 2H), 1.60 (s, 9H), 096-0.92 (m, 2H),0.02 (s, 9H). MS m/z [M+H]⁺ (ESI): 498.

Step 8

Into a 50-mL round-bottom flask, was placed a solution of tert-butylN-[5-([[(1R)-1-phenylethyl]amino]methyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazolo[4,3-b]pyridin-6-yl]carbamate(500 mg, 1.00 mmol, 1.00 equiv) in hydrochloric acid (15 mL, 3 N, 10.00equiv) and ethanol (15 mL). The solution was stirred for 25 min at 6° C.and diluted with water (100 mL). After the pH value of the solution wasadjusted to 10-11 with potassium carbonate, the resulting solution wasextracted with ethyl acetate (100 mL×3). The combined organic layerswere dried over anhydrous sodium sulfate. Filtration and concentrationunder vacuum afforded5-([[(1R)-1-phenylethyl]amino]methyl)-1-[[2-(trimethylsilyl)-ethoxy]methyl]-1H-pyrazolo[4,3-b]pyridin-6-amine(45I) as a yellow solid. MS m/z [M+H]⁺ (ESI): 398.

Step 9

Into a solution of5-([[(1R)-1-phenylethyl]amino]methyl)-1-[[2-(trimethylsilyl)-ethoxy]methyl]-1H-pyrazolo[4,3-b]pyridin-6-amine(370 mg, 0.93 mmol, 1.00 equiv) in dichloromethane (20 mL) was addedtriphosgene (110.7 mg, 0.37 mmol, 1.00 equiv) at ambient temperature.Stirred for 2 h, the reaction mixture was diluted with 100 mL of sat.NaHCO₃ and extracted with dichloromethane (100 mL×3). The combinedorganic layers were washed with brine (100 mL×3) and dried overanhydrous sodium sulfate. Filtration and concentration under vacuum gave6-(1-phenylethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-5,6-dihydro-1H-pyrazolo[3′,4′:5,6]pyrido[3,2-d]pyrimidin-7(8H)-one(45J) as a yellow solid. MS m/z [M+H]⁺ (ESI): 424.

Step 10

Into a 50-mL round-bottom flask was placed a solution of6-(1-phenylethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-5,6-dihydro-1H-pyrazolo[3′,4′:5,6]pyrido[3,2-d]pyrimidin-7(8H)-one(400 mg, 0.94 mmol, 1.00 equiv), silver sulfate (383.5 mg, 1.23 mmol,1.30 equiv) and iodine (312.2 mg, 1.23 mmol, 1.30 equiv) inethanol/methanol (1:1) (20 mL). After stirring for 1 h at 50° C., thereaction mixture was diluted with 100 mL of sat. Na₂SO₃ and extractedwith ethyl acetate (100 mL×3). The combined organic layers were washedwith brine (100 mL×3) and dried over anhydrous sodium sulfate. Uponfiltration and concentration under vacuum, the residue was purified by aflash chromatography on silica gel column eluting withdichloromethane/methanol (300:1-100:1) to afford3-iodo-6-(1-phenylethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-5,6-dihydro-1H-pyrazolo[3′,4′:5,6]pyrido[3,2-d]pyrimidin-7(8H)-one(45K) as a yellow solid. MS m/z [M+H]⁺ (ESI): 550.

Step 11

Into a 20-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a mixture of3-iodo-6-(1-phenylethyl)-1-((2-(trimethylsilyl)-ethoxy)methyl)-5,6-dihydro-1H-pyrazolo[3′,4′:5,6]pyrido[3,2-d]pyrimidin-7(8H)-one(130 mg, 0.24 mmol, 1.00 equiv), Pd(dppf)Cl₂ (14.6 mg, 0.02 mmol, 0.10equiv), potassium carbonate (98 mg, 0.71 mmol, 3.00 equiv) and(2-methylpyridin-4-yl)boronic acid (48.7 mg, 0.36 mmol, 1.50 equiv) indioxane:water (4:1) (5 mL). Stirred for 15 h at 80° C., the reactionmixture was diluted with water (100 mL) and extracted with ethyl acetate(100 mL×3). The combined organic layers were washed with brine (100mL×3) and dried over anhydrous sodium sulfate. After filtered andconcentrated under vacuum, the residue was purified by a flashchromatography on silica gel column eluting withdichloromethane/methanol (300:1-100:1) to afford3-(2-methylpyridin-4-yl)-6-(1-phenylethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-5,6-dihydro-1H-pyrazolo[3′,4′:5,6]pyrido[3,2-d]pyrimidin-7(8H)-one(45L) as a yellow solid. MS m/z [M+H]⁺ (ESI): 515.

Step 12

Into a 25-mL round-bottom flask, was placed a solution of3-(2-methylpyridin-4-yl)-6-(1-phenylethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-5,6-dihydro-1H-pyrazolo[3′,4′:5,6]pyrido[3,2-d]pyrimidin-7(8H)-one(60 mg, 0.12 mmol, 1.00 equiv) and TFA (1 mL) in dichloromethane (10mL). The resulting solution was stirred for 2 h at ambient temperature.Upon concentration under reduce pressure, the residue was purified byPrep-HPLC with the following conditions: [X Bridge Prep shield RP 18, 5μm, 19×150 mm; Mobile phase, water (0.05% ammoniumbicarbonate)/acetonitrile (30%˜75% in 10 min); Detector, 254 nm, 220 nm;RT=6.7 min.] to afford(R)-3-(2-methylpyridin-4-yl)-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[3′,4′:5,6]-pyrido-[3,2-d]pyrimidin-7(8H)-one(45) as light yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 13.38 (s,NH), 9.77 (s, 1H), 8.53-8.52 (d, J=4 Hz, 1H), 8.14-8.13 (d, J=4 Hz, 1H),8.11(s, 1H), 7.45-7.38 (m, 4H), 7.33-7.31 (m, 2H), 5.80-5.75 (m, 1H),4.65-4.61 (d, J=16 Hz, 1H), 4.10-4.06 (d, J=16 Hz, 1H), 2.53 (s, 3H),1.63-1.61 (d, J=8 Hz, 3H). MS m/z [M+H]⁺ (ESI): 385.

Example 46

(R)-4-(hydroxymethyl)-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one

In a manner similar to that described in Example 26 (Step 2), methyl5-bromo-6-chloro-1H-indazole-4-carboxylate (commercially available, CAS[1037841-34-1], also described in PCT Int Appl. 2008084717) was treatedwith trityl chloride and Hunig's base (DCM, room temperature, overnight)to provide methyl 5-bromo-6-chloro-1-trityl-1H-indazole-4-carboxylate(46B).

In a manner similar to that described in Example 35 (Step 1), 46B wasreacted with vinylboronic acid dibutyl ester and1,1′-bis(diphenylphosphino)ferrocene-palladium(ii)dichloridedichloromethane complex (dioxane-water, sodium bicarbonate, microwaved60 min at 80° C.) to provide methyl6-chloro-1-trityl-5-vinyl-1H-indazole-4-carboxylate (46C).

Compound 46C was reduced with LiAlH₄ (THF, 0° C., 60 min) and thenprotected with TBS-Cl (catalytic DMAP, imidazole, DMF, room temperature,overnight) to provide4-(((tert-butyldimethylsilyl)oxy)methyl)-6-chloro-1-trityl-5-vinyl-1H-indazole(46E).

Compound 46E was reacted with osmium tetraoxide and sodium periodate(water-THF, room temperature, overnight) to provide4-(((tert-butyldimethylsilyl)oxy)methyl)-6-chloro-1-trityl-1H-indazole-5-carbaldehyde(46F).

In a manner similar to that described in Example 26 (Step 4), 46F wasreacted with sodium triacetoxyborohydride and (R)-(+)-1-phenylethylamine (DCE) to provide(R)—N-((4-(((tert-butyldimethylsilyl)oxy)methyl)-6-chloro-1-trityl-1H-indazol-5-yl)methyl)-1-phenylethanamine(46G). LCMS: [M+H]⁺ m/z 672.

Compound 46G could be converted to compound 46 by the followingsequence:

(1) treatment with trimethylsilyl isocyanate (to provide(R)-1-((4-(((tert-butyldimethylsilyl)oxy)methyl)-6-chloro-1-trityl-1H-indazol-5-yl)methyl)-1-(1-phenylethyl)urea(46H));

(2) reaction with Brettphos palladacycle (in a manner similar to thatdescribed in Example 44, Step 1; to provide(R)-4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(1-phenylethyl)-1-trityl-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one(46I)); and

(3) final deprotection with TFA-EtSi₃H to provide(R)-4-(hydroxymethyl)-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one(in a manner similar to that described in Example 26, Step 8).

Example 47(R)-3-(6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one

In a manner similar to that described in Example 24 (Steps 6-7),compound 35F was sequentially reacted with4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine hydrochloride (47A)(RuPhos-G3-precatalyst((2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate), sodium tert-butoxide, overnight, 80° C.) and thenTFA/Et₃SiH to provide compound 47. LCMS: [M+H]⁺ m/z 431.

Table 1 below provides data for the compounds of the above examples aswell as additional examples. The compounds of the additional exampleswere prepared following procedures similar to those of the Exampleindicated in the “Route Used” column. No example number in the “RouteUsed” column means that the preparation is described in the writtenexamples above. The compounds of Examples (4)-(9), (11)-(15), (17)-(26),(30)-(37), (39)-(41), (43), (44), and (47) are trifluoroacetate salts.The compounds of Examples (27), (28) and (29) are formate salts.

TABLE 1 Exact Mass Route Example Structure and Name [M + M]+ Used 1

Calc'd 277, found 277 — 3-(2-methylpyridin-4-yl)-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one 2

Calc'd 355, found 355 — 6-bromo-3-(2-methylpyridin-4-yl)-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one 3

Calc'd 367, found 367 — 6-benzyl-3-(2-methylpyridin-4-yl)-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one 4

Calc'd 266, found 266 — 3-(1-methyl-1H-pyrazol-4-yl)-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one 5

Calc′d 186, found 186 1 1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one 6

Calc'd 344, found 344 2 6-bromo-3-(1-methyl-1H-pyrazol-4-yl)-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one trifluoroacetate 7

Calc'd 356, found 356 4 6-benzyl-3-(1-methyl-1H-pyrazol-4-yl)-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one 8

Calc'd 295; found 295 — 8-hydroxy-3-(2-methylpyridin-4-yl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinolin-7(8H)-one 9

Calc'd 293; found 293 — 3-(2-methylpyridin-4-yl)-5,6,7,9-tetrahydroazepino[3,2-f]indazol-8(1H)-one 10

Calc'd 402; found 402 — (R)-6-(1-(4-fluorophenyl)ethyl)-3-(2-methylpyridin-4-yl)-5,6-dihydro-1H- pyrazolo[4,3-g]quinazolin-7(8H)-one11

Calc'd 418; found 418 — 7-(4-fluorobenzyl)-9-hydroxy-3-(2-methylpyridin-4-yl)-5,6,7,9-tetrahydro-[1,3]diazepino[5,4-f]indazol-8(1H)-one 12

Calc'd 416; found 416 — (R)-7-(1-(4-fluorophenyl)ethyl)-3-(2-methylpyridin-4-yl)-5,6,7,9-tetrahydro-[1,3]diazepino[5,4-f]indazol-8(1H)-one 13

Calc'd 280; found 280 — 3-(2-methylpyridin-4-yl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one 14

Calc'd 370; found 370 14 6-benzyl-3-(2-methylpyridin-4-yl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one 15

Calc'd 438; found 438 — (R)-3-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-6-(1-phenylethyl)-1H-pyrazolo[4,3- g]quinazoline-5,7(6H,8H)-dione 16

Calc'd 426; found 426 10 3-(2-methylpyridin-4-yl)-6-(2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one 17

Calc'd 432; found 432 10 (S)-1-(4-fluorophenyl)-2-methoxy-N-(3-(2-methylpyridin-4-yl)-1H-azeto[3,2-f]indazol- 5(6H)-ylidene)ethanamine 18

Calc'd 400; found 400 10 6-(2-methoxybenzyl)-3-(2-methylpyridin-4-yl)5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin- 7(8H)-one 19

Calc'd 414; found 414 10 6-(2-methoxyphenethyl)-3-(2-methylpyridin-4-yl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin- 7(8H)-one 20

Calc'd 384; found 384 10 (R)-3-(2-methylpyridin-4-yl)-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin- 7(8H)-one2,2,2-trifluoroacetate 21

Calc'd 385; found 385 10 6-((6-methylpyridin-2-yl)methyl)-3-(2-methylpyridin-4-yl)-5,6-dihydro-1H- pyrazolo[4,3-g]quinazolin-7(8H)-one22

Calc'd 424; found 424 10 (R)-3-(2-methylpyridin-4-yl)-6-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)- one 23

Calc'd 398; found 398 15 (R)-3-(2-methylpyridin-4-yl)-6-(1-phenylethyl)-1H-pyrazolo[4,3-g]quinazoline-5,7(6H,8H)- dione 24

Calc'd 271; found 271 — 3-morpholino-1H-pyrazolo[4,3-g]quinolin-7(8H)-one 25

Calc'd 269; found 269 24 3-(piperidin-1-yl)-1H-pyrazolo[4,3-g]quinolin-7(8H)-one 26

Calc'd 424; found 424 — (R)-3-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3- g]quinazolin-7(8H)-one 27

Calc'd 395; found 395 26 (R)-5-(7-oxo-6-(1-phenylethyl)-5,6,7,8-tetrahydro-1H-pyrazolo[4,3-g]quinazolin-3- yl)picolinonitrile 28

Calc'd 401; found 401 26 (R)-3-(2-methoxypyrimidin-5-yl)-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3- g]quinazolin-7(8H)-one formate29

Calc'd 336; found 336 — (R)-3-(ethylamino)-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)- one 30

Calc'd 404; found 404 — 6-((R)-1-phenylethyl)-3-(((S)-1,1,1-trifluoropropan-2-yl)amino)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one 31

Calc'd [M + Na]⁺ 315; found 315 — (R)-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one 2,2,2- trifluoroacetate 32

Calc'd 308; found 308 — (R)-3-amino-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one 33

Calc'd 366; found 366 — (R)-methyl (7-oxo-6-(1-phenylethyl)-5,6,7,8-tetrahydro-1H-pyrazolo[4,3-g]quinazolin-3- yl)carbamate2,2,2-trifluoroacetate 34

Calc′d 350; found 350 33 (R)-N-(7-oxo-6-(1-phenylethyl)-5,6,7,8-tetrahydro-1H-pyrazolo[4,3-g]quinazolin-3- yl)acetamide 35

Calc'd 323, found 323 — (R)-3-methoxy-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one 36

Calc'd 367, found 367 35 (R)-3-(2-methoxyethoxy)-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)- one 37

Calc'd 353, found 353 35 (R)-3-(2-hydroxyethoxy)-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)- one 38

Calc′d 379, found 379 — 6-((R)-1-phenylethyl)-3-((tetrahydrofuran-3-yl)oxy)-5,6-dihydro-1H-pyrazolo[4,3- g]quinazolin-7(8H)-one 39

Calc'd 393, found 393 38 (R)-6-(1-phenylethyl)-3-((tetrahydro-2H-pyran-4-yl)oxy)-5,6-dihydro-1H-pyrazolo[4,3- g]quinazolin-7(8H)-one 40

Calc'd 333, found 333 — (R)-3-cyclopropyl-6-(1-phenylethyl)-5,6-dihydro-2H-pyrazolo[4,3-g]quinazolin-7(8H)- one 41

Calc'd 388, found 388 40 (R)-3-(2-fluoropyridin-4-yl)-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin- 7(8H)-one 42

Calc'd 378, found 378 — (R)-3-morpholino-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)- one 43

Calc'd 419, found 419 35 (R)-3-iodo-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazollin-7(8H)-one 44

Calc′d 322, found 322 — (R)-3-amino-6-(1-phenylethyl)-1H-pyrazolo[4,3-g]quinazoline-5,7(6H,8H)-dione 45

Calc'd 385, found 385 — (R)-3-(2-methylpyridin-4-yl)-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[3′,4′:5,6]- pyrido-[3,2-d]pyrimidin-7(8H)-one 46

(R)-4-(hydroxymethyl)-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)- one 47

Calc'd 431, found 431 — (R)-3-(6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-oneAssaysActive Human ERK2 (hERK2) Activity Assay:

Activated ERK2 activity was determined in an IMAP-FP assay (MolecularDevices). Using this assay format, the potency (IC₅₀) of each compoundwas determined from a 10 point (1:3 serial dilution, 3 μM startingcompound concentration) titration curve using the following outlinedprocedure. To each well of a black Corning 384-well plate (CorningCatalog #3575), 7.5 nL of compound (3333 fold dilution in final assayvolume of 25 μL) was dispensed, followed by the addition of 15 μL ofkinase buffer (tween containing kinase buffer, Molecular Devices)containing 0.0364 ng/mL (0.833 nM) of phosphorylated active hERK2enzyme. Following a 15 minute compound & enzyme incubation, eachreaction was initiated by the addition of 10 μL kinase buffer containing2.45 μM ERK2 IMAP substrate peptides (2.25 μM-unlabeled peptide and 200nM-labeled peptide, and 75 μM ATP. The final reaction in each well of 25μL consists of 0.5 nM hERK2, 900 nM unlabeled peptide, 80 nMlabeled-peptide, and 30 μM ATP. Phosphorylation reactions were allowedto proceed for 60 minutes and were immediately quenched by the additionof 60 μL IMAP detection beads (1:1000 dilutions) in IMAP binding buffer(Molecular Devices) with 24 mM NaCl. Plates were read on EnVision readerafter 60 minutes binding equilibration using Fluorescence Polarizationprotocol (Perkin Elmer).

Table 2 below provides the ERK 2 Human average IC₅₀ (in nM) data for thecompounds of Examples 4-43.

TABLE 2 Ex IC₅₀ 4 0.3 5 228 6 0.3 7 0.3 8 3.6 9 252 10 0.3 11 459 1272.0 13 0.6 14 0.5 15 1.7 16 4.8 17 0.7 18 0.8 19 2.3 20 0.3 21 0.6 2224 23 3.7 24 12 25 42 26 0.3 27 10 28 0.6 29 22 30 25 31 55 32 21 33 5.234 2.3 35 114 36 6.4 37 20 38 21 39 10 40 24 41 0.3 42 9.0 43 48

The compounds of Examples 44, 45, and 47 had an ERK 2 Human average IC₅₀(in nM) of 45, 0.5, and 24 respectively.

Active Mouse ERK2 (mERK2) Activity Assay:

Activated ERK2 activity was determined in an IMAP-FP assay (MolecularDevices). Using this assay format, the potency (IC₅₀) of each compoundwas determined from a 10 point (1:3 serial dilution, 3 μM startingcompound concentration) titration curve using the following outlinedprocedure. To each well of a black Corning 384-well plate (CorningCatalog #3575), 7.5 nL of compound (3333 fold dilution in final assayvolume of 25 μL) was dispensed, followed by the addition of 15 μL ofkinase buffer (tween containing kinase buffer, Molecular Devices)containing 0.0133 ng/mL (0.316 nM) of phosphorylated active mERK2enzyme. Following a 15 minute compound & enzyme incubation, eachreaction was initiated by the addition of 10 μL kinase buffer containing2.45 μM ERK2 IMAP substrate peptides (2.25 μM-unlabeled peptide and 200nM-labeled peptide, and 75 μM ATP. The final reaction in each well of 25μL consists of 0.19 nM mERK2, 900 nM unlabeled peptide, 80 nMlabeled-peptide, and 30 uM ATP. Phosphorylation reactions were allowedto proceed for 45 minutes and were immediately quenched by the additionof 60 μL IMAP detection beads (1:1000 dilutions) in IMAP binding buffer(Molecular Devices) with 24 mM NaCl. Plates were read on EnVision readerafter 60 minutes binding equilibration using Fluorescence Polarizationprotocol (Perkin Elmer).

Table 3 below provides the ERK 2 MAPK1 Mouse IC₅₀ (in nM) data for thecompounds of Examples 1-3.

TABLE 3 Ex IC₅₀ 1 0.4 2 0.2 3 0.2

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand variations thereof will be apparent to those of ordinary skill inthe art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

What is claimed is:
 1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein: Q is selectedfrom the group consisting of: —(CR³)— and N; X is selected from thegroup consisting of: NH and N—O; Y is —N(R⁹)—; Z is selected from thegroup consisting of: —C(═O)—, —C(R⁷R⁸)— and —C(R⁷R⁸)—C(R⁷R⁸)— whereineach R⁷ and each R⁸ is independently selected; R¹ is selected from thegroup consisting of: —NR¹²R¹³, —OR¹⁰, —O—(R¹⁰)—O—R¹⁰, —O—R¹⁰—OH, —O—R¹¹,(C₃-C₇)cycloalkyl, substituted (C₃-C₇)cycloalkyl, heteroaryl,substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl,(C₆-C₁₄)aryl, substituted (C₆-C₁₄)aryl, fused arylheteroaryl,substituted fused arylheteroaryl, fused heterocycloalkylheteroaryl, andsubstituted fused heterocycloalkylheteroaryl; and wherein saidsubstituted R¹ groups are substituted with 1 to 3 substituentsindependently selected from the group consisting of: —(C₁-C₆)alkyl,halo, CN, —OH, —OR¹⁰, —CF₃, ═O, —NH₂, —NH(C₁-C₆)alkyl,—S(O)₂(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl, —((C₁-C₆)alkyl)OH,—(C₃-C₆)cycloalkyl-S—(C₃-C₆)cycloalkyl, —N((C₁-C₆)alkyl)₂ wherein eachalkyl is independently selected, —C(O)O—(C₁-C₆)alkyl, —C(O)OH, —OCF₃,—C(O)NH(C₁-C₆)alkyl, heteroaryl, —(C₁-C₆)alkyl)-O—(C₁-C₆)alkyl, fusedheteroarylaryl-, heterocycloalkyl, and heterocycloalkenyl; and whereinthe alkyl moieties of the R¹ groups, are optionally substituted with 1to 3 substituents independently selected from the group consisting of:(C₁-C₆)alkoxy, halo, CN, —OH, ═O, —CF₃, —NH₂, —NH(C₁-C₆)alkyl,—S(O)₂(C₁-C₆)alkyl, fused heteroarylaryl-, heterocycloalkyl, andheterocycloalkenyl; and wherein said heteroaryl moiety of said R¹ groupsis a 5-10 membered ring comprising 1-3 heteroatoms independentlyselected from the group consisting of: N, O and S, and wherein theremaining ring atoms are carbon (and wherein said heteroaryl definitionapplies to the heteroaryl moieties in the R¹ fused heteroarylheteroaryl,substituted fused heteroarylheteroaryl, fused arylheteroaryl, fusedheterocycloalkyl-heteroaryl, substituted fusedheterocycloalkylheteroaryl, and fused heteroarylaryl- groups); andwherein said heterocycloalkyl moiety of said R¹ groups is a 3-10membered ring comprising 1-3 heteroatoms independently selected from thegroup consisting of: N, O and S, and wherein the remaining ring atomsare carbon (and wherein said heterocycloalkyl definition applies to theheterocycloalkyl moieties in the R¹ fused heterocycloalkylheteroaryl andsubstituted fused heterocycloalkylheteroaryl groups; and wherein saidfused arylheteroaryl moiety of said R¹ groups comprises a C₆-C₁₀ arylfused to a heteroaryl, as defined above, wherein the aryl and theheteroaryl have 2 ring atoms in common; R² is selected from the groupconsisting of: H, halo, —NH₂, —OH and —(C₁-C₃)alkyl; R³ is selected fromthe group consisting of: H, halo, (C₁-C₆alkyl), and (C₁-C₆alkyl)substituted with 1-2 —OH groups, —(C₃-C₆ cycloalkyl),—(C₁-C₆alkyl)-O—(C₁-C₆alkyl), —(C₁-C₆alkyl)-N(C₁-C₆alkyl)₂ wherein eachalkyl is independently selected, and -(C₁-C₆alkyl)-heterocycloalkyl,wherein said heterocycloalkyl is as defined above for R¹; each R⁶, R⁷and R⁸ is independently selected from the group consisting of: H, halo,(C₆-C₁₄)aryl(C₁-C₆)-alkyl-, and substituted (C₆-C₁₄)aryl(C₁-C₆)alkyl-,heteroaryl, substituted heteroaryl, heteroaryl(C₁-C₆)alkyl-, substitutedheteroaryl(C₁-C₆)alkyl-, fused (C₃-C₇)cycloalkyl(C₆-C₁₄)aryl,substituted fused (C₃-C₇)cycloalkyl(C₆-C₁₄)aryl, fusedheterocycloalkyl(C₆-C₁₄)aryl, substituted fusedheterocycloalkyl(C₆-C₁₄)aryl; wherein said substituted R⁶, R⁷, R⁸moieties are substituted with 1-3 substitutents independently selectedfrom the group consisting of: halo, (C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C₁-C₆)alkyl; and wherein said heteroaryl moiety and saidheterocycloalkyl moiety is as defined above in R¹; R⁹ is selected fromthe group consisting of: (C₆-C₁₀)aryl(C₁-C₆)alkyl-, and substituted(C₆-C₁₄)aryl(C₁-C₆)alkyl-, heteroaryl(C₁-C₆)alkyl-, substitutedheteroaryl(C₁-C₆)alkyl-, fused heterocycloalkyl(C₆-C₁₄)aryl, substitutedfused heterocycloalkyl(C₆-C₁₄)aryl; wherein said substituted R⁹ moietiesare substituted with 1-3 substitutents independently selected from thegroup consisting of: halo, OH, CN, CF₃, (C₁-C₆)alkyl, (C₁-C₆)alkyl-O—(C₁-C₆)alkyl; and wherein said heteroaryl moiety and saidheterocycloalkyl moiety is as defined above for R¹; each R¹⁰ isindependently selected from the group consisting of: C₁-C₆alkyl; R¹¹ isselected from the group consisting of: a 4-7 membered heterocycloalkylring comprising 1-3 heteroatoms independently selected from the groupconsisting of: O, S and N; and R¹² and R¹³ are independently selectedfrom the group consisting of: H, (C₁-C₆)alkyl, —C(O)OR¹⁰, —C(O)R¹⁰; saidalkyl group optionally substituted with 1-4 substitutents independentlyselected from the group consisting of halo.
 2. The compound of claim 1,wherein Q is —(CR³)—.
 3. The compound of claim 1, wherein Z is—C(R⁷R⁸)—.
 4. The compound of claim 1, wherein Z is —C(R⁷R⁸)—C(R⁷R⁸)—.5. The compound of claim 1, wherein R⁷ and R⁸ are H.
 6. The compound ofclaim 1, wherein Ring B is selected from the group consisting of: (d2),(d3), (e2), and (e3).
 7. The compound of claim 1, wherein Ring B isselected from the group consisting of: (d2), (e2), and (e3).
 8. Thecompound of claim 7 wherein R⁷ and R⁸ are H.
 9. The compound of claim 1,wherein R⁹ is selected from the group consisting of:heteroaryl(C₁-C₆)alkyl-, substituted heteroaryl(C₁-C₆)alkyl-,(C₆-C₁₀)aryl(C₁-C₆)alkyl-, substituted (C₆-C₁₀)aryl(C₁-C₆)alkyl-, fusedheterocycloalkyl(C₆-C₁₀)aryl, and fused substitutedheterocycloalkyl(C₆-C₁₀)aryl.
 10. The compound of claim 1, wherein R⁹ isselected from the group consisting of: (g1), (g2), (g3), (g4), (g6),(g7), (g8), (g9), (g10), (g11), (g12), (g13), (g14), and (g15).
 11. Thecompound of claim 1, wherein R¹ is selected from the group consistingof: —NR¹²R¹³, —OR¹⁰, —O—(R¹⁰)—O—R¹⁰, —O—R¹⁰—OH, (C₃-C₇)cycloalkyl,substituted (C₃-C₇)cycloalkyl, heterocycloalkyl, substitutedheterocycloalkyl, —OR¹¹, heteroaryl, substituted heteroaryl, fusedarylheteroaryl, and fused substituted arylheteroaryl.
 12. The compoundof claim 1, wherein R¹ is selected from the group consisting of: —NH₂,—NHCH₂CH₃, —NHCH(CH₃)C(F)₃, —NHC(O)OCH₃, —NHC(O)CH₃, —OCH₃,—OCH₂CH₂OCH₃, —OCH₂CH₂OH, —(CH₂)₃—O—CH₃, cyclopropyl, (f1), (f2), (f3),(f4), (f8), (f9), (f11), and (f12).
 13. A compound selected from thegroup consisting of compounds (10)-(12), (14)-(23), (26)-(30),(32)-(42), (44), (45), and (47), or a pharmaceutically acceptable saltthereof.
 14. A pharmaceutical composition comprising a compound of claim1, and a pharmaceutically acceptable carrier.